Clinical Pharmacokinetics
and Pharmacodynamics
Larry A. Bauer
1
KEY CONCEPTS
Clinical pharmacokinetics is the discipline that describes
the absorption, distribution, metabolism, and elimination of
drugs in patients requiring drug therapy.
2 Clearance is the most important pharmacokinetic parameter
because it determines the steady-state concentration for a
given dosage rate. Physiologically, clearance is determined
by blood flow to the organ that metabolizes or eliminates
the drug and the efficiency of the organ in extracting the
drug from the bloodstream.
3 The volume of distribution is a proportionality constant
that relates the amount of drug in the body to the serum
concentration. The volume of distribution is used to
calculate the loading dose of a drug that will immediately
achieve a desired steady-state concentration. The value of
the volume of distribution is determined by the physiologic
volume of blood and tissues and how the drug binds in
blood and tissues.
4 Half-life is the time required for serum concentrations to
decrease by one-half after absorption and distribution are
complete. It is important because it determines the time
required to reach steady state and the dosage interval. Half-
life is a dependent kinetic variable because its value depends
on the values of clearance and volume of distribution.
5 The fraction of drug absorbed into the systemic circulation
after extravascular administration is defined as its
bioavailability.
6 Most drugs follow linear pharmacokinetics, whereby steady-
state serum drug concentrations change proportionally with
long-term daily dosing.
7 Some drugs do not follow the rules of linear
pharmacokinetics. Instead of steady-state drug
concentration changing proportionally with the dose, serum
concentration changes more or less than expected. These
drugs follow nonlinear pharmacokinetics.
8 Pharmacokinetic models are useful to describe data sets, to
predict serum concentrations after several doses or different
routes of administration, and to calculate pharmacokinetic
constants such as clearance, volume of distribution, and
half-life. The simplest case uses a single compartment to
represent the entire body.
9 Factors to be taken into consideration when deciding on
the best drug dose for a patient include age, gender, weight,
ethnic background, other concurrent disease states, and
other drug therapy.
10 Cytochrome P450 is a generic name for the group of
enzymes that are responsible for most drug metabolism
oxidation reactions. Several P450 isozymes have been
Copyright © 2014 McGraw-Hill Education. All rights reserved.
e|CHAPTER 5
identified, including CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4.
11 Membrane transporters are protein molecules concerned
with the active transport of drugs across cell membranes.
The importance of transport proteins in drug bioavailability,
elimination, and distribution is continuing to evolve.
A principal transport protein involved in the movement
of drugs across biologic membranes is P-glycoprotein.
P-glycoprotein is present in many organs, including the
gastrointestinal (GI) tract, liver, and kidney. Other transport
protein families include the organic cation transporters,
the organic anion transporters, and the organic anion
transporting polypeptides.
12 When deciding on initial doses for drugs that are renally
eliminated, the patient’s renal function should be assessed.
A common, useful way to do this is to measure the patient’s
serum creatinine concentration and convert this value
into an estimated creatinine clearance (CLcr est). For drugs
that are eliminated primarily by the kidney (≥60% of the
administered dose), some agents will need minor dosage
adjustments for CLcr est between 30 and 60 mL/min (0.50 and
1.00 mL/s), moderate dosage adjustments for CLcr est between
15 and 30 mL/min (0.25 and 0.50 mL/s), and major dosage
adjustments for CLcr est less than 15 mL/min (0.25 mL/s).
Supplemental doses of some medications also may be
needed for patients receiving hemodialysis if the drug is
removed by the artificial kidney or for patients receiving
hemoperfusion if the drug is removed by the hemofilter.
13 When deciding on initial doses for drugs that are hepatically
eliminated, the patient’s liver function should be assessed.
The Child-Pugh score can be used as an indicator of a
patient’s ability to metabolize drugs that are eliminated by
the liver. In the absence of specific pharmacokinetic dosing
guidelines for a medication, a Child-Pugh score equal to 8
or 9 is grounds for a moderate decrease (∼25%) in the initial
daily drug dose for agents that are metabolized primarily
hepatically (≥60%), and a score of 10 or greater indicates
that a significant decrease in the initial daily dose (∼50%) is
required for drugs that are metabolized mostly hepatically.
14 For drugs that exhibit linear pharmacokinetics, steady-
state drug concentration (Css) changes proportionally with
dose (D). To adjust a patient’s drug therapy, a reasonable
starting dose is administered for an estimated three to five
half-lives. A serum concentration is obtained, assuming that
it will reflect Css. Independent of the route of administration,
the new dose (Dnew) needed to attain the desired Css(Css,new) is
calculated as Dnew = Dold(Css,new/Css,old), where Dold and Css,old are
the old dose and old Css, respectively.
51
 52

15 If it is necessary to determine the pharmacokinetic constants
eTable 5-1 Selected Therapeutic Ranges
for a patient to individualize his or her dose, a small
Drug Therapeutic Range
pharmacokinetic evaluation is conducted in the individual.
Additionally, Bayesian computer programs that aid in the Digoxin 0.5–2 ng/mL or mg/L
0.6–2.6 nmol/L
individualization of therapy are available for many different
drugs. Lidocaine 1.5–5 mcg/mL or mg/L
6.4–21 μmol/L

16 Pharmacodynamics is the study of the relationship between
Procainamide/N-acetylprocainamide 10–30 mcg/mL or mg/L
the concentration of a drug and the response obtained (total) 42–127 μmol/L
SECTION

in a patient. If pharmacologic effect is plotted against

concentration for most drugs, a hyperbola results with an Quinidine 2–5 mcg/mL or mg/L
asymptote equal to the maximum attainable effect. 6–15 μmol/L
Amikacina 20–30 mcg/mL or mg/L (peak)
34–51 μmol/L (peak)
  

<5 mcg/mL or mg/L (trough)

1 CLINICAL PHARMACOKINETICS <9 μmol/L (trough)

AND PHARMACODYNAMICS: Gentamicin, tobramycin, netilmicina 5–10 mcg/mL or mg/L (peak)

10–21 μmol/L (peak)
Foundation Issues

INTRODUCTION <2 mcg/mL or mg/L (trough)

<4 μmol/L (trough)
Pharmacokinetic concepts have been used successfully by phar- Vancomycin 20–40 mcg/mL or mg/L (peak)
macists to individualize patient drug therapy for about a quarter 14–28 μmol/L (peak)
century. Pharmacokinetic consultant services and individual clini- 5–15 mcg/mL or mg/L (trough)b
3–10 μmol/L (trough)b
cians routinely provide patient-specific drug-dosing recommenda-
tions that increase the efficacy and decrease the toxicity of many Chloramphenicol 10–20 mcg/mL or mg/L
31–62 μmol/L
medications. Laboratories routinely measure patient serum or
plasma samples for many drugs, including antibiotics (e.g., ami- Lithium 0.6–1.4 mEq/L
0.6–1.4 mmol/L
noglycosides and vancomycin), theophylline, antiepileptics (e.g.,
Carbamazepine 4–12 mcg/mL or mg/L
phenytoin, carbamazepine, valproic acid, phenobarbital, and etho-
17–51 μmol/L
suximide), methotrexate, lithium, antiarrhythmics (e.g., lidocaine
Ethosuximide 40–100 mcg/mL or mg/L
and digoxin), and immunosuppressants (e.g., cyclosporine and
283–708 μmol/L
tacrolimus). Combined with a knowledge of the disease states and
Lamotrigine 2–20 mcg/mL
conditions that influence the disposition of a particular drug, kinetic
8–80 μmol/L
concepts can be used to modify doses to produce serum drug con-
Oxcarbazepine (as monohydroxy 3–35 mcg/mL
centrations that result in desirable pharmacologic effects without
derivative)
unwanted side effects. This narrow range of concentrations within
Phenobarbital 15–40 mcg/mL or mg/L
which the pharmacologic response is produced and adverse effects
65–172 μmol/L
prevented in most patients is defined as the therapeutic range of
Phenytoin/Fosphenytoin 10–20 mcg/mL or mg/L
the drug. eTable 5-1 lists the therapeutic ranges for commonly used
40–79 μmol/L
medications.
Primidone 5–12 mcg/mL or mg/L
Although most individuals experience favorable effects with
23–55 μmol/L
serum drug concentrations in the therapeutic range, the effects of a
Valproic acid 50–100 mcg/mL or mg/L
given serum concentration can vary widely among individuals. Cli-
347–693 μmol/L
nicians should never assume that a serum concentration within the
Theophylline 10–20 mcg/mL or mg/L
therapeutic range will be safe and effective for every patient. The
56–111 μmol/L
response to the drug, such as the number of seizures a patient experi-
Cyclosporine (blood) 150–400 ng/mL or mcg/L
ences while taking an antiepileptic agent, should always be assessed 125–333 nmol/L
when serum concentrations are measured.
Throughout this chapter, abbreviations for various pharmaco- a
Using a multiple dose per day conventional dosage schedule.
b
For patients with pneumonia or other life-threatening infections due to multi-
kinetic parameters are used frequently. eTable 5-2 lists commonly drug resistant bacteria trough concentrations as high as 15–20 mcg/mL or mg/L
used abbreviations. (10–14 μmol/L) have been recommended.

CLINICAL PHARMACOKINETIC The vascular system generally provides the “transportation”

CONCEPTS
1 Clinical pharmacokinetics is the discipline that describes the
absorption, distribution, metabolism, and elimination of drugs in
patients requiring drug therapy. When a drug is administered extra-
vascularly to patients, it must be absorbed across biologic mem-
branes to reach the systemic circulation. If the drug is given orally,
the drug molecules must pass through the gastrointestinal (GI) tract
wall into capillaries. For transdermal patches, the drug must pen-
etrate the skin to enter the vascular system. In general, the pharma-
cologic effect of the drug is delayed when it is given extravascularly
because time is required for the drug to be absorbed into the vas-
cular system.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
for the drug molecule to its site of activity. After the drug reaches
the systemic circulation, it can leave the vasculature and penetrate
the various tissues or remain in the blood. If the drug remains
in the blood, it may bind to endogenous protein, such as albumin
and α1-acid glycoprotein. This binding usually is reversible, and an
equilibrium is created between protein-bound drug and unbound
drug. Unbound drug in the blood provides the driving force for dis-
tribution of the agent to body tissues. If unbound drug leaves the
bloodstream and distributes to tissue, it may become tissue-bound,
it may remain unbound in the tissue, or if the tissue can metabolize
or eliminate the drug, it may be rendered inactive and/or eliminated
from the body. If the drug becomes tissue-bound, it may bind to
the receptor that causes its pharmacologic or toxic effect or to a
 53
eTable 5-2 Pharmacokinetic Abbreviations
Abbreviation Definition
CL Clearance
k0 IV infusion rate
CSS Steady-state concentration
D Dose

e|CHAPTER  
C
τ Dosage interval
F Fraction of drug absorbed into the systemic circulation
Q Blood flow
E Extraction ratio
fb Fraction of drug in the blood that is unbound
Clint Intrinsic clearance
Css, u Steady-state concentration of unbound drug
t 5
VD Volume of distribution
eFigure 5-1  Typical serum concentration-time curve following

Clinical Pharmacokinetics and Pharmacodynamics

LD Loading dose
MD Maintenance dose a continuous IV infusion.
t1/2 Half-life
k Elimination rate constant
ka Absorption rate constant
example, if a drug dose were doubled from 300 to 600 mg daily, the
α Distribution rate constant patient’s serum drug concentration would double.
β Terminal rate constant When a drug is given by continuous IV infusion, serum con-
t’ Postinfusion time centrations increase until an equilibrium is established between the
T Duration of infusion drug dosage rate and the rate of drug elimination. At that point, the
AUC Area under serum or blood concentration-versus- rate of drug administration equals the rate of drug elimination, and
time curve the serum concentrations remain constant (eFig. 5-1). For example,
Vmax Maximum rate of drug metabolism if a patient were receiving a continuous IV infusion of theophylline
at 40 mg/h, the theophylline serum concentration would increase
Km Serum concentration at which the rate of metabolism
equals Vmax/2 until the patient’s body was eliminating theophylline at 40 mg/h.
Cmax Maximum serum or blood concentration
When serum drug concentrations reach a constant value, steady
state is achieved.
Cmin Minimum serum or blood concentration
If the drug is given at intermittent dosage intervals, such as
DR Dosage rate 250 mg every 6 hours, steady state is achieved when the serum-­
P-gp P-glycoprotein concentration-versus-time curves for each dosage interval are
superimposable. The amount of drug eliminated during the dosage
interval equals the dose.

nonspecific binding site that causes no effect. Again, tissue binding
is usually reversible, so that the tissue-bound drug is in equilibrium
with the unbound drug in the tissue.
Certain organs—such as the liver, GI tract wall, and lung—­
possess enzymes that metabolize drugs. The resulting metabolite
may be inactive or have a pharmacologic effect of its own. The
blood also contains esterases, which cleave ester bonds in drug mol-
ecules and generally render them inactive.
Drug metabolism usually occurs in the liver through one or
both of two types of reactions. Phase I reactions generally make the
drug molecule more polar and water soluble so that it is prone to
elimination by the kidney. Phase I modifications include oxidation,
hydrolysis, and reduction. Phase II reactions involve conjugation to
form glucuronides, acetates, or sulfates. These reactions generally
inactivate the pharmacologic activity of the drug and may make it
more prone to elimination by the kidney.
Other organs have the ability to eliminate drugs or metabolites
from the body. The kidney can excrete drugs by glomerular filtra-
tion or by such active processes as proximal tubular secretion. Drugs
also can be eliminated via bile produced by the liver or air expired
by the lungs.
Linear Pharmacokinetics
6 Most drugs follow linear pharmacokinetics; serum drug con-
centrations change proportionally with long-term daily dosing. For
Copyright © 2014 McGraw-Hill Education. All rights reserved.
Bioavailability and Bioequivalence
5 When drugs are administered extravascularly, drug molecules
must be released from the dosage form (dissolution) and pass
through several biologic barriers before reaching the vascular sys-
tem (absorption). The fraction of drug absorbed into the systemic
circulation (F) after extravascular administration is defined as its
bioavailability and can be calculated after single IV and extravas-
cular doses as1
Div(AUC0 – ∞)
F=
D(AUCiv,0 – ∞)
where D and Div are the extravascular and IV doses, respectively, and
AUCiv,0-∞ and AUC0-∞ are the IV and extravascular areas under the
serum- or blood-concentration-versus-time curves, respectively, from
time zero to infinity. The AUC represents the body’s total exposure to
the drug and is a function of the fraction of the drug dose that enters
the systemic circulation via the administered route and clearance
(eFig. 5-2). When F is less than 1 for a drug administered extravascu-
larly, either the dosage form did not release all the drug contained in
it, or some of the drug was eliminated or destroyed (by stomach acid
or other means) before it reached the systemic circulation.
When the extravascular dose is administered orally, part of
the dose may be metabolized by enzymes or removed by transport
proteins contained in the GI tract wall or liver before it reaches
the systemic circulation.2,3 This occurs commonly when drugs
 54
16
14
12
Concentration (mcg/mL)
10
8 to the organ that metabolizes (liver) or eliminates (kidney) the drug
SECTION
6 bloodstream.5 Efficiency is measured using an extraction ratio (E),
AUC
4 extracting organ (Cout) from the concentration in the blood entering
2
1 0
0 5 10 15 20
Time (h)
Foundation Issues
eFigure 5-2  Area under the concentration-versus-time curve
(AUC) after the administration of an extravascular dose. The
AUC is a function of the fraction of drug dose that enters the
systemic circulation and clearance. AUCs measured after IV and
extravascular doses can be used to determine bioavailability for
the extravascular dose.
have a high liver extraction ratio or are subject to GI tract wall
metabolism because, after oral administration, the drug must pass
through the GI tract wall and into the portal circulation of the liver.
Transport proteins are also present in the GI tract wall that can
actively pump drug molecules that already have been absorbed
back into the lumen of the GI tract. P-glycoprotein (P-gp) is the
primary transport protein that interferes with drug absorption by
this mechanism. For example, if an orally administered drug is
100% absorbed from the GI tract but has a hepatic extraction ratio
of 0.75, only 25% of the original dose enters the systemic circula-
tion. This first-pass effect through the liver and/or GI tract wall is
avoided when the drug is given by other routes of administration.
The computation of F does not separate loss of oral drug metabo-
lized by the first-pass effect and drug not absorbed by the GI tract.
Special techniques are needed to determine the fraction of drug
absorbed orally for drugs with high liver extraction ratios or sub-
stantial gut wall metabolism.
Two different dosage forms of the same drug are considered to
be bioequivalent when the AUC0-∞, maximum serum or blood con-
centrations (Cmax), and the times that Cmax occurs (tmax) are neither
clinically nor statistically different. When this occurs, the serum-
concentration-versus-time curves for the two dosage forms should
be superimposable and identical. Bioequivalence studies have
become very important as expensive drugs become available in
less costly generic form. Most bioequivalence studies involve 18 to
25 healthy adults who are given the brand-name product and the
generic product in a randomized, crossover study design.
Clearance
2 Clearance (CL) is the most important pharmacokinetic param-
eter because it determines the steady-state drug concentration (Css)
for a given dosage rate. When a drug is given at a continuous IV
infusion rate equal to k0, the Css is determined by the quotient of k0
and CL (Css = k0/CL). If the drug is administered as individual doses
(D) at a given dosage interval (τ), the average Css over the dosage
interval is given by the equation4
F(D/τ)
Css =
CL
Copyright © 2014 McGraw-Hill Education. All rights reserved.
where F is the fraction of dose absorbed into the systemic vascu-
lar system. The average Css over the dosage interval is the Css that
would have occurred had the same dose been given as a continuous
IV infusion (e.g., 300 mg every 6 hours would produce an average
Css equivalent to the actual Css produced by a continuous infusion
administered at a rate of 50 mg/h).
Physiologically, clearance is determined by (a) blood flow (Q)
and (b) the efficiency of the organ in extracting the drug from the
calculated by subtracting the concentration in the blood leaving the
the organ (Cin) and then dividing the result by Cin:
Cin – Cout
25
E=
Cin
Clearance for that organ is calculated by taking the product of Q and
E (CL = QE). For example, if liver blood flow equals 1.5  L/min,
and the drug’s extraction ratio is 0.33, hepatic clearance equals
0.5  L/min. Total clearance is computed by summing all the indi-
vidual organ clearance values. Clearance changes occur in patients
when the blood flow to extracting organs changes or when the
extraction ratio changes. Vasodilators such as hydralazine and
nifedipine increase liver blood flow, whereas chronic heart failure
(CHF) and hypotension can decrease hepatic blood flow. Extrac-
tion ratios can increase when enzyme inducers increase the amount
of drug-metabolizing enzyme. Extraction ratios may decrease if
enzyme inhibitors inhibit drug-metabolizing enzymes or necrosis
causes loss of parenchyma.
Intrinsic Clearance
The extraction ratio also can be thought of in terms of the unbound
fraction of drug in the blood (fb), the intrinsic ability of the extract-
ing organ to clear unbound drug from the blood (CLint), and blood
flow to the organ (Q):6,7
fb(CLint)
E=
Q + fb(CLint)
By substituting this equation for E, the clearance equation
becomes
Q[ f b(CLint)]
CL =
Q + f b(CLint)
Clearance changes will occur when blood flow to the clear-
ing organ changes (in conditions where blood flow is reduced,
e.g., shock and CHF, or where blood flow is increased, e.g.,
administration of medications, such as vasodilators, and resolu-
tion of shock or CHF), binding in the blood changes (e.g., if the
concentration of binding proteins is low or highly protein-bound
drugs are displaced), or intrinsic clearance of unbound drug
changes (e.g., when metabolizing enzymes are induced or inhib-
ited by other drug therapy or functional organ tissue is destroyed
by disease processes).
If CLint is large (enzymes have a high capacity to metabolize
the drug), the product of fb and CLint is much larger than Q. When
fb(CLint) is much greater than Q, the sum of Q and fb(CLint) in the
denominator of the clearance equation almost equals fb(CLint):
fb(CLint) ≈ Q + fb(CLint)
Substituting this expression in the denominator of the clear-
ance equation and canceling common terms leads to the following
expression for drugs with a large CLint: CL ≈ Q. In this case, clear-
ance of the drug is equal to blood flow to the organ; such drugs

are called high-clearance drugs and have large extraction ratios.
Propranolol, verapamil, morphine, and lidocaine are examples of
high-clearance drugs. High-clearance drugs such as these typically
exhibit high first-pass effects when administered orally.
If CLint is small (enzymes have a limited capacity to metabo-
lize the drug), Q is much larger than the product of fb and CLint.
When Q is much greater than fb(CLint), the sum of Q and fb(CLint) in
the denominator of the clearance equation becomes almost equal to
Q: Q ≈ Q + fb(CLint). Substituting this expression in the denomina-
tor of the clearance equation and canceling common terms leads
to the following expression for drugs with a small CLint: CL ≈
fb(CLint). In this case, clearance of the drug is equal to the product
of the fraction unbound in the blood and the intrinsic ability of the
organ to clear unbound drug from the blood; such drugs are known
as low-clearance drugs and have small extraction ratios. Warfarin,
theophylline, diazepam, and phenobarbital are examples of low-
clearance drugs.
As mentioned previously, the concentration of unbound drug
in the blood is probably more important pharmacologically than
the total (bound plus unbound) concentration. The unbound drug
in the blood is in equilibrium with the unbound drug in the tissues
and reflects the concentration of drug at its site of action. There-
fore, the pharmacologic effect of a drug is thought to be a function
of the concentration of unbound drug in the blood. The unbound
steady-state concentration (Css,u) can be calculated by multiplying
Css and fb: Css,u = Css fb. The effect that changes in Q, fb, and CLint
have on Css,u and therefore on the pharmacologic response of a drug
depends on whether a high- or low-clearance drug is involved.
Because CL = Q for high-clearance drugs, a change in fb or CLint
does not change CL or Css(Css = k0/CL). However, a change in
unbound drug fraction does alter Css,u(Css,u = fbCss), thereby affect-
ing the pharmacologic response. Plasma protein-binding displace-
ment drug interactions can be very important clinically, but they
are also dangerous because the changes in Css,u are not reflected in
changes in Css for high-clearance drugs. Because laboratories usu-
ally measure only total concentrations (concentrations of unbound
drug are difficult to determine), the interaction is hard to detect. If
CLint changes for high-clearance drugs, CL, Css, Css,u, and pharma-
cologic response do not change. Changes in Q cause a change in
CL; changes in Css, Css,u, and drug response are indirectly propor-
tional to changes in CL.
For low-clearance drugs, total clearance is determined by
unbound drug fraction and intrinsic clearance: CL = fb(CLint).
A change in Q does not change CL, Css, Css,u, or pharmacologic
response. However, a change in fb or CLint does alter CL and Css (Css =
k0/CL). Changes in CLint will cause a proportional change in CL.
Changes in Css, Css,u, and drug response are indirectly propor-
tional to changes in CL. Altering fb for low-clearance drugs pro-
duces interesting results. A change in fb alters CL and Css (Css  =
k0/CL). Because CL and Css change in opposite directions with
changes in fb, Css,u (Css,u = fbCss) and pharmacologic response do not
change with alterations in the fraction of unbound drug in the blood.
For example, a low-clearance drug is administered to a patient until
steady-state is achieved:
CL = f b(CLint)
k0
Css =
CL
Suppose that another drug is administered to the patient that
displaces the first drug from plasma-protein-binding sites and
doubles fb (fb now equals 2fb). CL doubles because of the protein-
binding displacement [2CL = 2fb(CLint)], and Css decreases by one-
half because of the change in clearance [½(Css) = k0/(2Cl)]. Css,u
does not change because even though fb is doubled, Css decreased
by one-half (Css,u = fbCss). The potential for error in this situation is
Copyright © 2014 McGraw-Hill Education. All rights reserved.
55
that clinicians may increase the dose of a low-clearance drug after
a protein-binding displacement interaction because Css decreased.
Because Css,u and the pharmacologic effect do not change, the dose
should remain unaltered. Plasma protein binding decreases occur
commonly in patients taking phenytoin. Low albumin concentra-
tions (as in trauma or pregnant patients), high concentrations of
endogenous plasma protein-binding displacers (as with high con-
e|CHAPTER  
centrations of bilirubin), or plasma protein-binding drug interac-
tions (as with concomitant therapy with valproic acid) can result
in subtherapeutic total phenytoin concentrations. Despite this fact,
unbound phenytoin concentrations usually are within the therapeu-
tic range, and often the patient is responding appropriately to treat-
ment. Thus, in these situations, unbound rather than total phenytoin
serum concentrations should be monitored and used to guide future
therapeutic decisions.
5
Clearances for Different Routes of
Clinical Pharmacokinetics and Pharmacodynamics
Elimination and Metabolic Pathways
Clearances for individual organs can be computed if the excretion
the organ produces can be obtained. For example, renal clearance
can be calculated if urine is collected during a pharmacokinetic
experiment. The patient empties his or her bladder immediately
before the dose is given. Subsequent urine production is collected
until the last serum concentration (Clast) is obtained. Renal clearance
(CLR) is computed by dividing the amount of drug excreted in the
urine by AUC0–t,last. Biliary and other clearance values are computed
in a similar fashion.
Clearances also can be calculated for each metabolite that is
formed from the parent drug. This computation is particularly useful
in drug-interaction studies to determine which metabolic pathway is
stimulated or inhibited. In the following metabolic scheme, the par-
ent drug (D) is metabolized into two different metabolites (M1, M2)
that subsequently are eliminated by the kidney (M1R, M2R):
CLFM1 kidney
D M1 M1R
CLFM2
M2 kidney M2R
To compute the formation clearance of M1 and M2 (CLFM1,
CLFM2), urine would be collected for five or more half-lives after a
single dose or during a dosage interval at steady state. The amount
of metabolite eliminated in the urine is then determined. The frac-
tion of the dose (in moles, because the molecular weights of the
parent drug and metabolites are not equal) eliminated by each meta-
bolic pathway (fM1 = M1R/D and fM2 = M2R/D) can then be computed.
Formation clearance for each pathway can be calculated using the
following equations: CLFM1 = fM1CLM and CLFM2 = fM2CLM, where
CLM is the metabolic clearance for the parent drug.
Volume of Distribution
3 The volume of distribution (VD) is a proportionality constant
that relates the amount of drug in the body to the serum concen-
tration (amount in body = CVD). VD is used to calculate the loading
dose (LD) of a drug that will immediately achieve a desired Css
(LD = CssVD). However, in practice, the patient’s own VD is not
known at the time the loading dose is administered. In this case,
an average VD is assumed and used to calculate a loading dose.
Because the patient’s VD is almost always different from the aver-
age VD for the drug, a loading dose does not attain the calculated
Css, but it ideally achieves a therapeutic concentration. As usual,
steady-state conditions are achieved in three to five half-lives for
the drug.
 56
C0
12
Slope = −k
2.303
log C
SECTION
6
t1/2
1 Dose
t
Foundation Issues
eFigure 5-3  Calculation of the half-life of a drug following IV
bolus dosing.
The numeric value for the volume of distribution is determined
by the physiologic volume of blood and tissues and how the drug
binds in blood and tissues:8
VD = Vb + (fb/ft)Vt
where Vb and Vt are the volumes of blood and tissues, respectively,
and fb and ft are the fractions of unbound drug in blood and tissues,
respectively.
Half-Life
4 Half-life (t1/2) is the time required for serum concentrations to
decrease by one-half after absorption and distribution are complete.
It takes the same amount of time for serum concentrations to drop
from 200 to 100 mg/L as it does for concentrations to decline from
2 to 1 mg/L (eFig. 5-3).
Half-life is important because it determines the time required
to reach steady state and the dosage interval. It takes approximately
three to five half-lives to reach steady-state concentrations during
continuous dosing. In three half-lives, serum concentrations are at
∼90% of their ultimate steady-state values. Because most serum drug
assays have an ∼10% error, it is difficult to differentiate concentra-
tions that are within 10% of each other. For this reason, many clini-
cians consider concentrations obtained after three half-lives to be Css.
Half-life is also used to determine the dosage interval for
a drug. For example, it may be desirable to maintain maximum
steady-state concentrations at 20 mg/L and minimum steady-state
concentrations at 10 mg/L. In this case, it would be necessary to
administer the drug every half-life because the minimum desirable
concentration is one-half the maximum desirable concentration.
Half-life is a dependent kinetic variable because its value
depends on the values of CL and VD.8 The equation that describes
the relationship among the three variables is t1/2 = 0.693VD/CL.
Changes in t1/2 can result from a change in either VD or CL; a change
in t1/2 does not necessarily indicate that CL has changed. Half-life
can change solely because of changes in VD. The elimination rate
constant (k) is related to the half-life by the following equation: k =
0.693/t1/2. Both the half-life and elimination rate constant describe
how quickly serum concentrations decrease in the serum or blood.
Nonlinear Pharmacokinetics
Michaelis-Menten Kinetics
7 Some drugs do not follow the rules of linear pharmacokinetics.
Instead of Css and AUC increasing proportionally with dose, serum
Copyright © 2014 McGraw-Hill Education. All rights reserved.
Linear
Michaelis–Menten
Css or AUC
Nonlinear protein binding
or autoinduction
eFigure 5-4  Relationship of dose and steady-state drug
concentration (Css) or area under the concentration-versus-time
curve (AUC) under linear and nonlinear conditions.
concentrations change more or less than expected (eFig. 5-4). One
explanation for the greater-than-expected increase in Css and AUC
after an increase in dose is that the enzymes responsible for the
metabolism or elimination of the drug may start to become satu-
rated. When this occurs, the maximum rate of metabolism (Vmax)
for the drug is approached. This is called Michaelis-Menten kinet-
ics. The serum concentration at which the rate of metabolism equals
Vmax/2 is Km. Practically speaking, Km is the serum concentration
at which nonproportional changes in Css and AUC start to occur
when the dose is increased. The Michaelis-Menten constants (Vmax
and Km) determine the dosage rate (DR) needed to maintain a given
Css: DR = VmaxCss/(Km + Css). Most drugs eliminated by the liver are
metabolized by enzymes but still appear to follow linear kinetics.
The reason for this disparity is that the therapeutic range for most
drugs is well below the Km of the enzyme system that metabolizes
the agent. The therapeutic range is higher than Km for some com-
monly used drugs. The average Km for phenytoin is about 4 mg/L
(16 μmol/L). The therapeutic range for phenytoin is usually 10 to
20 mg/L (40  to 79 μmol/L). Most patients experience Michaelis-
Menten kinetics while taking phenytoin.
Nonlinear Protein Binding
Another type of nonlinear kinetics can occur if Css and AUC increase
less than expected after an increase in dose of a low-clearance drug.
This usually indicates that plasma protein-binding sites are start-
ing to become saturated, so that fb increases with increases in the
dose (see eFig. 5-4). For a low-clearance drug, CL depends on the
values of fb and CLint (CL = fbCLint). When a dosage increase takes
place, fb increases because nearly all plasma protein-binding sites
are occupied, and no binding sites are available. If fb increases,
CL increases, and Css increases less than expected with the dos-
age change (Css = k0/CL). However, Css,u increases proportionally
with the dose because Css,u depends on CLint for low-clearance drugs
(Css,u = k0/CLint). Valproic acid9 and disopyramide10 both follow satu-
rable protein-binding pharmacokinetics.
Autoinduction
For some drugs, clearance increases as the dose or concentration of
the drug increases. In this situation, increasing the drug dose or con-
centration increases the ability of the enzyme system to eliminate
the compound and to clear the drug from the body. This is usually
accomplished by inducing the enzyme system responsible for the
metabolism of the drug, so that the intrinsic clearance of the drug

One compartment
k0,ka, or k A
1 log
IV bolus
Two compartments
k12
k0,ka, or
1 2
IV bolus
k21
k10
eFigure 5-5  Visual representations of one- and two-compartment
drug-distribution models.
increases. Because the drug itself is causing the induction effect, this
process is called autoinduction. For some drugs, such as carbamaze-
pine,11 the autoinduction effect is continuous within the typical dos-
age range, which produces a curve for the dose versus Css or AUC
plot similar to nonlinear protein binding (see eFig. 5-4). Detailed
pharmacokinetic studies are conducted to differentiate between non-
linear protein binding and autoinduction when dose versus Css or
AUC plots systematically deviate below the linear line.
Pharmacokinetic Models and Equations
8 Pharmacokinetic models are useful to describe data sets, to pre-
dict serum concentrations after several doses or different routes of
administration, and to calculate pharmacokinetic constants such
as CL, VD, and t1/2.12 Compartmental models depict the body as
one or more discrete compartments to which a drug is distributed
and/or from which a drug is eliminated. The shape of the serum-­
concentration-versus-time curve determines the number of com-
partments in the pharmacokinetic model and the equation used in
computations (eFig. 5-5). First-order rate constants, known as micro-
constants, describe the rate of transfer from one compartment to
another. Each compartment also has its own VD. For clinical dosage
adjustment purposes using drug concentrations, a one-compartment
model is the most commonly used pharmacokinetic model.
One-Compartment Model
The simplest case uses a single compartment to represent the entire
body (see eFig. 5-5). The drug enters the compartment by continu-
ous IV infusion (k0), absorption from an extravascular site with an
absorption rate constant of ka, or IV bolus (D). After an IV bolus,
serum concentrations decline in a straight line when plotted on
semilogarithmic coordinates (see eFig. 5-3). The slope of the line is
-k/2.303; t1/2 can be computed by determining the time required for
concentrations to decrease by one-half (t1/2 = 0.693/k). The equation
that describes the data is C = (D/VD)e−kt. VD is calculated by divid-
ing the IV dose by the y intercept (the concentration at time zero,
C0) of the graph. CL is computed by taking the product of k and VD.
Once VD and k are known, concentrations at any time after the dose
can be computed [C = (D/VD)e−kt].
When an extravascular dose is given, one-compartment-model
serum concentrations rise during absorption, reach Cmax, then
decrease in a straight line with a slope equal to –k/2.303. The equa-
tion that describes the data is C = {(FDka)/[VD(ka – k)]}(e−kt – e−kat),
where F is the fraction of the dose absorbed into the systemic circu-
lation. The absorption rate constant (ka) is obtained using the method
of residuals.
The method of residuals is used to obtain the individual rate
constants (eFig. 5-6). A is determined by extrapolating the termi-
nal slope to the y axis; k can be obtained by calculating the slope
Copyright © 2014 McGraw-Hill Education. All rights reserved.
57
A
residual −ka
Slope =
2.303
t
10
e|CHAPTER  
log C
−k
Slope =
2.303
5
t 1/2
5
t
Clinical Pharmacokinetics and Pharmacodynamics
eFigure 5-6  Calculation of the half-life of a drug following oral,
intramuscular, or other extravascular dosing route. Inset shows
calculation of the absorption rate constant (ka) using the method
of residuals.
or t1/2 and using the formulas given for the IV bolus case. At each
time point in the absorption portion of the curve, the concentration
value from the extrapolated line is noted and called the extrapolated
concentration. For each point, the actual concentration is subtracted
from the extrapolated concentration to compute the residual con-
centration. When the residual concentrations are plotted on semi-
logarithmic coordinates (see eFig. 5-6, inset), a line with y intercept
equal to A and slope equal to -ka/2.303 is obtained. When these val-
ues are calculated, they can be placed into the equation (C = Ae−kt -
Ae−kat, where A = FDka/[VD(ka - k)]) and used to compute the serum
concentration at any time after the extravascular dose. The inter-
cepts and rate constants also can be used to compute CL and VD:
CL = FD/(A/k - A/ka) and VD = CL/k, where F is the fraction of the
dose absorbed into the systemic circulation.
During a continuous IV infusion, the serum concentrations in
a one-compartment model change according to the following func-
tion: C = (k0/CL)(1 - e−kt). If the infusion has been running for more
than three to five half-lives, the patient will be at steady state, and
CL can be calculated (CL = k0/Css). When the infusion is discontin-
ued, serum concentrations appear to decline in a straight line when
plotted on semilogarithmic paper with a slope of -k/2.303. VD is
computed by dividing CL by k (eFig. 5-7).
DC infusion
Css
log C
Slope =
−k
2.303
t
3–5 t 1/2
eFigure 5-7  Achievement of steady-state serum concentrations
after three to five half-lives of a drug. Note the elimination phase
after discontinuance of the infusion.
 58
Multicompartment Model R
−α
After an IV bolus dose, serum concentrations often decline in 7 Slope =
2.303
two or more phases. During the early phases, the drug leaves the log
bloodstream by two mechanisms: (a) distribution into tissues and residual 3.5
3.5
(b) metabolism and/or elimination. Because the drug is leaving the
t1/2α
bloodstream through these two mechanisms, serum concentrations
decline rapidly. After tissues and blood are in equilibrium, only t
metabolism and elimination remove the drug from the blood. Dur-

log C
−β
SECTION

ing this terminal phase, serum concentrations decline more slowly. Slope =
2.303
The half-life is measured during the terminal phase by determining
the time required for concentrations to decline by one-half. 6
After an IV bolus dose, serum concentrations decrease as if the S
3
drug were being injected into a central compartment that not only
  

t1/2β
metabolizes and eliminates the drug but also distributes the drug to
1 one or more other compartments. Of these multicompartment mod-
els, the two-compartment model is encountered most commonly
t
(see eFig. 5-5). After an IV bolus injection, serum concentrations
Foundation Issues

DC infusion
decrease in two distinct phases, described by the equation
D(α – k21) –αt D(k21 – β ) –β t eFigure 5-9  Calculation of α and β half-lives following a steady-
C= e + e state infusion. Inset shows calculation of the distribution rate
V D1(α – β ) V D1(α – β )
constant (α) using the method of residuals.
or C = Ae−αt + Be−βt, where k21 is the first-order rate constant that
reflects the transfer of the drug from compartment 2 to compart-
ment 1, VD is the VD of compartment 1, A = D(α - k21)/[VD (α - β )]
1 1 If serum concentrations of a drug given as a continuous IV
and B = D(k21 - β )/[VD1(α - β )]. The rate constants α and β found
infusion decline in a biphasic manner after the infusion is discontin-
in the exponents of the equations describe the distribution and elimi-
ued, a two-compartment model describes the data set (eFig. 5-9).13,14
nation of the drug, respectively (eFig. 5-8). A and B are the y inter-
In this instance, the postinfusion concentrations decrease accord-
cepts of the lines that describe drug distribution and elimination,
ing to the equation C = Re−αt′ + Se−βt′, where t′ is the postinfusion
respectively, on the log concentration-versus-time plot.
time (t’ = 0 when infusion is discontinued), and R, S, α, and β are
The residual line is calculated as before using the method of
determined from the postinfusion concentrations using the method
residuals (see eFig. 5-8, inset). The terminal line is extrapolated to
of residuals with the y axis set at t′ = 0. R and S are used to compute
the y axis, and extrapolated concentrations are determined for each
A and B. A and B are the y intercepts that would have occurred had
time point. Because actual concentrations are greater in this case,
the total dose given during the infusion (D = k0T) been administered
residual concentrations are calculated by subtracting the extrapo-
as an IV bolus dose:
lated concentrations from the actual concentrations. When plotted
on semilogarithmic paper, the residual line has a y intercept equal RDα
A=
to A. The slope of the residual line is used to compute α (slope = k0(1 – e–αT )
-α/2.303). With the rate constants (α and β ) and the intercepts
SDβ
(A and B), concentrations can be calculated for any time after the IV B=
bolus dose (C = Ae−αt + Be−βt), or pharmacokinetic constants can be k0(1 – e–βT )
computed: CL = D/[(A/α) + (B/β )], VD,β = CL/β, VD,ss = {D[(A/α 2) +
(B/β 2)]}/[(A/α) + (B/β )]2. where T is the duration of infusion. Once A, B, α, and β are known,
the equations for an IV bolus are used to compute the pharma-
cokinetic constants. Often, when a drug is given as an IV bolus
or continuous IV infusion, a two-compartment model is used to
A describe the data, but when the same agent is given extravascu-
−α
5 Slope = larly, a one-compartment model applies.15 In this case, distribu-
2.303
log tion occurs during the absorption phase, so a distribution  phase
residual 2.5 is not observed.
t1/2α
Volumes of Distribution
t
in Multicompartment Models
Two different VD values are needed as proportionality constants for
log C

B 20 −β drugs that require multicompartment models to describe the serum-

Slope =
2.303 concentration-versus-time curve. The VD that is used to compute
10 the amount of drug in the body during the terminal (β ) portion of
the curve is called VD,β (amount of drug in body = VD,β C). During
t1/2β a continuous IV infusion at steady state, VD,ss is used to compute
the amount of drug in the body (amount of drug in body = VD,ssC).
VD,ss is also the VD that can be computed using the physiologic vol-
t umes of blood and tissues and the ratio of unbound drug in blood
to that in tissues [VD,ss = Vb + (fb/ft)Vt]. Because the value of VD,β
eFigure 5-8  Calculation of α and β half-lives following IV changes when CL changes, VD,ss should be used to indicate if drug
dosing. Inset shows calculation of the distribution rate constant distribution changes during pharmacokinetic or drug-interaction
(α) using the method of residuals. experiments.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 59
Multiple Dosing and Steady-State Equations eTable 5-3A Cytochrome P450 Enzyme Family
Any of these compartmental equations can be used to determine and Selected Substrates
serum concentrations after multiple doses. The multiple-dosing CYP1A2 CYP2E1
factor (1 - e−nKτ)/(1 - e−Kτ), where n is the number of doses, K is Acetaminophen Enflurane
the appropriate rate constant, and τ is the dosage interval, is simply Caffeine Ethanol
Ondansetron Halothane
multiplied by each exponential term in the equation, substituting
Tacrine Isoflurane
the rate constant of each exponent for K. Time (t) is set at 0 at

e|CHAPTER  
Theophylline CYP3A4
the beginning of each dosage interval. For example, a single-dose R-warfarin Alfentanil
two-compartment IV bolus is calculated as follows: C = Ae−αt + Zileuton Alprazolam
Be−βt. Thus, the equation for a multiple-dose two-compartment IV CYP2C9 Astemizole
bolus is Candesartan Carbamazepine
Diclofenac Cyclosporine
1 – e–nατ 1 – e–nβτ Ibuprofen Diltiazem
C = Ae–αt + Be–βt Losartan Erythromycin
1 – e–ατ 1 – e–βτ
5
Naproxen Felodipine
A single-dose one-compartment IV bolus is calculated as C = Phenytoin Itraconazole
Tolbutamide Ketoconazole
(D/VD)e−kt. For a multiple-dose one-compartment IV bolus, the con-
Valsartan Lidocaine
centration is C = (D/VD)e−kt[(1 - e−nkτ)/(1 - e−kτ)].

Clinical Pharmacokinetics and Pharmacodynamics

S-warfarin Lovastatin
At steady state, the number of doses becomes large, e−nKτ CYP2C19 Midazolam
approaches zero, and the multiple-dosing factor equals 1/(1 - e−Kτ). Diazepam Nifedipine
Therefore, the steady-state versions of the equations are simpler Lansoprazole Quinidine
(S)-mephenytoin Simvastatin
than their multiple-dose counterparts: Tacrolimus
Nelfinavir
Verapamil
Ae–αt Be–βt Omeprazole
C= + Pantoprazole Ziprasidone
1–e –ατ
1 – e–βτ
Voriconazole
and CYP2D6
Carvedilol
(D/VD)e –kt
Codeine
C=
1 – e–kτ Debrisoquine
Dextromethorphan
for a steady-state two-compartment IV bolus and a steady-state one- Encainide
compartment IV bolus, respectively. Fluoxetine
Haloperidol
(S)-metoprolol
Use of Pharmacokinetic Concepts for Paroxetine
Propafenone
Individualization of Drug Therapy Risperidone
Thioridazine
9 Many factors must be taken into consideration when deciding
Venlafaxine
on the best drug dose for a patient. For example, the age of the
patient is important because the dose (in milligrams per kilogram)
for pediatric patients may be higher and for geriatric patients may
be lower than the typically prescribed dose for young adults. Gender
also can be a factor because male and female patients metabolize CYP2D6 oxidizes debrisoquine.16 These subsets of the CYP enzyme
and eliminate some drugs differently. Patients who are significantly family are also responsible for the metabolism of several other drugs
obese or cachectic also may require different drug doses because of (CYP2D6: many tricyclic antidepressants, codeine, (S)-metoprolol;
clearance and volume of distribution changes. Other drug therapy CYP2C19: most proton pump inhibitors, sertraline, voriconazole).
that could cause drug interactions needs to be considered. Disease CYP2C9, CYP2C19, and CYP2D6 isozymes appear to be under
states and conditions may alter the drug-dosage regimen for a genetic control. As a consequence, there are “poor metabolizers”
patient. Three disease states that deserve special mention are CHF, who have a defective mutant gene for the isozyme, cannot manu-
renal disease, and hepatic disease. Renal and hepatic diseases cause facture a fully functional isozyme, and therefore cannot metabolize
loss of organ function and decreased drug elimination and metabo- the drug substrate very well. “Extensive metabolizers” have the
lism. CHF causes decreased blood flow to organs that clear the drug standard gene for the isozyme and metabolize the drugs normally.
from the body. Poor metabolizers usually are a minority of the general population.
Many drug compounds are racemic mixtures of stereoiso- They may achieve toxic concentrations of a drug when usual doses
mers. In most cases, one of the isomers is more pharmacologically are prescribed for them or, if the active drug moiety is a metabo-
active than the other isomer, and each isomer may exhibit differ- lite, may fail to have any pharmacologic effect from the drug. The
ent pharmacokinetic properties. Warfarin, propranolol, verapamil, ethnic background of the patient can affect the likelihood that the
and ibuprofen are all racemic mixtures of stereoisomers. Some drug patient will be a poor metabolizer.16 For example, the incidence of
interactions inhibit or increase the elimination of only one stereo- poor metabolizers for CYP2D6 is ∼5% to 10% for whites and ∼0%
isomer. The importance of the drug interaction depends on which to 1% for Asians, whereas for CYP2C19, poor metabolizers make
isomer is affected. Other drugs, such as dextromethorphan, levo- up ∼3% to 6% of the white population and ∼20% of the Asian popu-
floxacin, and diltiazem, are composed of just one stereoisomer. lation. Approximately 7% of the whites are poor metabolizers for
10 Genetics also plays a role in drug metabolism. Cytochrome CYP2C9 substrates.
P450 is a generic term for the group of enzymes that are responsible Other cytochrome P450 isozymes have been isolated.16
for most drug metabolism oxidation reactions. Several cytochrome CYP1A2 is the enzyme that is responsible for the demethylation
P450 (CYP) isozymes have been identified that are responsible for of caffeine and theophylline; CYP2C9 metabolizes phenytoin,
the metabolism of many important drugs (eTable 5-3A). CYP2C19 tolbutamide, losartan, and ibuprofen; some antiretroviral protease
is responsible for aromatic hydroxylation of (S)-mephenytoin, and inhibitors, cyclosporine, nifedipine, lovastatin, simvastatin, and
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 60
atorvastatin are metabolized by CYP3A4; and ethanol is a sub- eTable 5-3B Membrane Transport Proteins
strate for CYP2E1. It is important to recognize that a drug may and Selected Substrates
be metabolized by more than one cytochrome P450 isozyme.
P-Glycoprotein (P-gp) OAT1B1
Although most tricyclic antidepressants are hydroxylated by
Sites: Intestinal enterocytes, kidney Site: Hepatocytes (sinusoidal)
CYP2D6, N-­demethylation probably is mediated by a combina- proximal tubule, hepatocytes Bosentan
tion of CYP2C19, CYP1A2, and CYP3A4. Acetaminophen appears (canalicular), brain endothelia Olmesartan
to be metabolized by both CYP1A2 and CYP2E1. The 4-hydroxy Alfentanil Repaglinide
metabolite of propranolol is produced by CYP2D6, but side-chain Aliskiren Statins
Ambrisentan Valsartan
oxidation of propranolol is probably a product of CYP2C19. The
SECTION

Atorvastatin OAT1
CYP3A enzyme family comprises ∼90% of the drug-metabolizing Azithromycin Sites: Kidney proximal tubule,
enzyme present in the intestinal wall but only ∼30% of the drug- Cetirizine placenta
metabolizing enzyme found in the liver. The remainder of hepatic Citalopram Acyclovir
Clopidogrel
drug-metabolizing enzyme is ∼20% for the CYP2C family, ∼13% Cephradine
Cyclosporine
  

for CYP1A2, ∼7% for CYP2E1, and ∼2% for CYP2D6. Ciprofloxacin
Daunorubicin
1
Methotrexate
Understanding which cytochrome P450 isozyme is responsible Dexamethasone Zidovudine
for the metabolism of a drug is extraordinarily useful in predict- Digoxin
Diltiazem OAT3
ing and understanding drug interactions. Some drug-metabolism Sites: Kidney proximal tubule,
Doxorubicin
Foundation Issues

inhibitors and inducers are highly selective for certain CYP iso- Erythromycin choroid plexus, brain endothelia
zymes.16  Quinidine is an extremely potent inhibitor of the CYP2D6 Etoposide Bumetanide
enzyme system;16 a single 50-mg dose of quinidine can change a Fexofenadine Cefaclor
Glyburide Ceftizoxime
rapid metabolizer of debrisoquine into a poor metabolizer. Cipro- Furosemide
Indinavir
floxacin and zileuton inhibit, whereas tobacco and marijuana smoke NSAIDs
Imatinib
induces, CYP1A2. Some drugs that are enzyme inhibitors are also Loperamide OCT1
substrates for that same enzyme system and appear to cause drug Loratadine Sites: Hepatocytes (sinusoidal),
interactions by being a competitive inhibitor. For example, eryth- Lovastatin intestinal enterocytes
romycin is both a substrate for and an inhibitor of CYP3A4. Obvi- Morphine Metformin
Nelfinavir Oxaliplatin
ously, if one knows that a new drug is metabolized by a given CYP Olanzapine OCT2
enzyme system, it is logical to assume that the new drug will exhibit Ondansetron Sites: Kidney proximal tubule,
drug interactions with the known inducers and inhibitors of that Paclitaxel neurons
CYP isozyme. Quinidine Amantadine
Raltegravir Amiloride
11 The importance of membrane transport proteins in drug
Ranolazine Metformin
bioavailability, elimination, and distribution is now better under- Risperidone Pindolol
stood.16–18 Membrane transporters are protein molecules con- Rifampin Procainamide
cerned with the active transport of drugs across cell membranes Ritonavir Ranitidine
(eTable 5-3B). This results in the transfer of drug molecules either Saquinavir
Tacrolimus
out of or into cells. Membrane transporters have been found in the Telaprevir
intestine, liver, kidney, and the blood-brain barrier. Verapamil
A principal transport protein involved in the movement of Vinblastine
drugs across biologic membranes is P-gp. P-gp is present in many Vincristine
organs, including the GI tract, liver, and kidney. If a drug is a sub- OAT, organic anion transporter; OCT, organic cation transporter; NSAIDs,
strate for P-gp, its oral absorption may be decreased when P-gp nonsteroidal antiinflammatory drugs.
transports drug molecules that have been absorbed back into the
GI tract lumen. In the liver, some drugs are transported by P-gp
from the blood into the bile, where the drug is eliminated by biliary
secretion. Similarly, some drugs eliminated by the kidney are trans-
Selection of Initial Drug Doses
ported from the blood into the urine by P-gp. Digoxin is a substrate 12 When deciding on initial doses for drugs that are eliminated
of P-gp. Other possible mechanisms for drug interactions are when renally, the patient’s renal function should be assessed. A com-
two drugs that are substrates for P-gp compete for transport by the mon, useful way to do this is to measure the patient’s serum cre-
protein and when a drug is an inhibitor or inducer of P-gp. Drug atinine concentration and convert this value into a CLcr est. Serum
interactions involving inhibition of P-gp decrease drug transporta- creatinine values alone should not be used to assess renal function
tion in these organs and potentially can increase GI absorption of an because they do not include the effects of age, body weight, or gen-
orally administered drug, decrease biliary secretion of the drug, or der. The Cockcroft-Gault equation19 is probably the most widely
decrease renal elimination of drug molecules. The drug interaction used method to estimate creatinine clearance (CLcr) (in milliliters
between amiodarone and digoxin probably involves all three of these per minute) in adults (age 18 years or older) who are within ∼30%
mechanisms; this explains why digoxin concentrations increase so of their ideal body weight and have stable renal function:
dramatically in patients receiving amiodarone. Many drugs that are (140 – age)BW
metabolized by CYP3A4 are also substrates for P-gp, and some of Men: CLcr est =
Scr × 72
the drug interactions attributed to inhibition of CYP3A4 may be a
result of decreased drug transportation by P-gp. Drug interactions 0.85(140 – age)BW
Women: CLcr est =
involving induction of P-gp have the opposite effect in these organs Scr × 72
and may decrease GI absorption of an orally administered drug,
increase biliary secretion of the drug, or increase renal elimination where BW is body weight (in kilograms), age is the patient’s age
of drug molecules. (in  years), 0.85 is a correction factor to account for lower mus-
Other membrane transporter families include the organic cation cle mass in women, and Scr is serum creatinine (in milligrams
transporters (OCT family), organic anion transporters (OAT family), per deciliter). For children, the following estimation equations
and the organic anion transporting polypeptides (OATP family). are available according to the age of the child20 age 0 to 1 year:
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 61
CLcr  est (in mL/min/1.73 m2) = (0.45 × Lt)/Scr; age 1 to 20 years: eTable 5-4 Theophylline Pharmacokinetic Parameters
CLcr  est (in mL/min/1.73 m2) = (0.55 × Lt)/Scr, where Lt is patient for Selected Disease States/Conditions
length in centimeters. (To use these equations, Scr expressed in
Mean Clearance Mean Dose
μmol/L must first be divided by 88.4 to obtain conventional units Disease State/Condition (mL/min/kg) (mg/kg/h)
of mg/dL. Conversion of CLcr to units of mL/s/m2 requires multi-
Children 1–9 years old 1.4 0.8
plication of CLcr expressed in milliliters per minute per 1.73 m2 by
Children 9–12 years old or adult 1.25 0.7
0.00963.) Other methods to determine CLcr est for obese adults21 and
smokers

e|CHAPTER  
patients with rapidly changing renal function22 are available. Creati-
Adolescents 12–16 years old or 0.9 0.5
nine is a by-product of muscle breakdown in the body, so none of
elderly smokers (>65 years)
these estimation methods work well in patients with muscle disease,
Adult nonsmokers 0.7 0.4
such as multiple sclerosis, or diseases that alter muscle mass, such
as cachexia, malnutrition, cancer, or spinal cord injury. Nomograms Elderly nonsmokers (>65 years) 0.5 0.3
that adjust initial doses according to a patient’s renal function are Decompensated CHF, cor 0.35 0.2
available for several drugs, including digoxin,23 vancomycin,24 and pulmonale, cirrhosis
the aminoglycoside antibiotics.25
For drugs that are eliminated primarily by the kidney (≥60% of
Mean volume of distribution = 0.5 L/kg.
CHF, chronic heart failure.
5
the administered dose), some agents will need minor dosage adjust- Data from Reference 52.

Clinical Pharmacokinetics and Pharmacodynamics

ments for CLcr est between 30 and 60 mL/min (0.50 and 1.00 mL/s),
moderate dosage adjustments for CLcr est between 15 and 30 mL/min
(0.25 and 0.50 mL/s), and major dosage adjustments for CLcr est less
than 15 mL/min (0.25 mL/s). Specific recommendations for dos-
age adjustments of other drugs for patients with renal disease are
available.26,27 Supplemental doses of some medications also may be
needed for patients receiving hemodialysis if the drug is removed by
the artificial kidney or for patients receiving hemoperfusion if the
drug is removed by the hemofilter.27
13 A similar assessment of liver function should be made for
drugs that are metabolized hepatically. Unfortunately, there is no
single test that can estimate liver drug-metabolism capacity accu-
rately, and those that are used do not always prove accurate. High
aminotransferase (aspartate aminotransferase [AST] and alanine
aminotransferase [ALT]) and alkaline phosphatase concentrations
usually indicate acute hepatic cellular damage and do not establish
poor liver drug metabolism reliably. Abnormal values for three tests
that usually indicate that drugs will be metabolized poorly by the
liver are high serum bilirubin concentration, low serum albumin con-
centration, and a prolonged prothrombin time. Bilirubin is metabo-
lized by the liver, and albumin and clotting factors are manufactured
by the liver, so aberrant values for all three of these tests are a more
reliable indicator of abnormal liver drug metabolism. The Child-
Pugh score,28 a widely used clinical classification for liver disease
that incorporates clinical signs and symptoms (ascites and hepatic
encephalopathy), in addition to these three laboratory tests, can be
used as an indicator of a patient’s ability to metabolize drugs that are
eliminated by the liver. A score in excess of 10 suggests very poor
liver function. As a general rule, patients with cirrhosis have the most
severe decreases in liver drug metabolism. Patients with acute or
chronic hepatitis often retain relatively normal or slightly decreased
hepatic drug-metabolism capacity. In the absence of specific phar-
macokinetic dosing guidelines for a medication, a Child-Pugh score
equal to 8 to 9 is grounds for a moderate decrease (∼25%) in initial
daily drug dose for agents that are metabolized primarily (≥60%)
hepatically, and a score of 10 or greater indicates that a significant
decrease in initial daily dose (∼50%) is required for drugs that are
metabolized mostly by the liver. As in any patient with or without
liver dysfunction, initial doses are meant as starting points for dosage
titration based on patient response and avoidance of adverse effects.
Because there are no good markers of liver function, clinicians
have come to rely on pharmacokinetic parameters derived in vari-
ous patient populations to compute initial doses of drugs that are
eliminated hepatically. eTable 5-4 contains average pharmacokinetic
parameters for theophylline in several disease states. Initial doses of
many liver-metabolized drugs are computed by determining which
disease states and/or conditions the patient has that are known to
alter the kinetics of the drug and by using these average pharmacoki-
netic constants to calculate doses. The patient is then monitored for
Copyright © 2014 McGraw-Hill Education. All rights reserved.
therapeutic and adverse effects, and drug serum concentrations are
obtained to ensure that concentrations are appropriate and to adjust
doses, if necessary. The following computations illustrate the esti-
mated IV loading dose and the IV continuous infusion necessary
to achieve a theophylline concentration of 10 mg/L (10 mcg/mL;
55.5 μmol/L) for a 55-year-old man, weighing 70 kg (154 lb), with
liver cirrhosis (mean kinetic parameters obtained from eTable 5-4):
VD = (0.5 L/kg)(70 kg) = 35 L
LD = CssVD = (10 mg/L)(35 L)
= 350 mg theophylline infused over 20 to 30 min
(0.35 mL/min/kg)(70 kg)(60 min/h)
CL(in L/h) =
1000 mL/L
= 1.5 L/h
k0 = CssCL = (10 mg/L)(1.5 L/h)
= 15 mg/h of theophylline to begin after loading dose
is given
If theophylline is to be given as the aminophylline salt
form, each dose would need to be changed to reflect the fact that
­aminophylline contains only 85% theophylline (LD = 350 mg of
­theophylline/0.85 = 410 mg of aminophylline infused over 20 to
30 minutes, k0 = 15 mg/h of theophylline/0.85 = 18 mg/h of amino-
phylline to begin after loading dose is given).
Heart failure is often overlooked as a disease state that can alter
drug disposition. Severe heart failure decreases cardiac output and
therefore reduces liver blood flow. Theophylline,29 lidocaine,30 and
drugs with high extraction ratios are compounds whose clearance
declines with decreased liver blood flow. Initial dosages of these
drugs should be reduced in patients with moderate to severe heart
failure (New York Heart Association class III or IV) by 25% to 50%
until steady-state concentrations and response can be determined.
Use of Steady-State Drug
Concentrations
14 Serum drug concentrations are readily available to clinicians to
use as guides for the individualization of drug therapy. The thera-
peutic ranges for several drugs have been identified, and it is likely
that new drugs also will be monitored using serum concentrations.
Although several individualization methods have been advocated
for specific drugs, one simple, reliable method is used commonly.
For drugs that exhibit linear pharmacokinetics, Css changes pro-
portionally with the dose. To adjust a patient’s drug therapy, a rea-
sonable starting dose is administered for an estimated three to five
half-lives. A serum concentration is obtained, assuming that it will
reflect Css. Independent of the route of administration, the new dose
 62
(Dnew) needed to attain the desired Css (Css,new) is calculated: Dnew = 10
C max,ss
Dold(Css,new/Css,old), where Dold and Css,old are the old dose and old Css,
respectively. To use this method, Css,old must reflect steady-state con- t1/2

Concentration (mcg/mL)
ditions. Often patients are noncompliant with regard to their drug
dosage and therefore are not at steady state. This occurs not only
in outpatients but also in hospital inpatients. Inpatients can spit out 1
oral doses or alter the infusion rates on IV pump rates after the nurse Cmin,ss
∗
Cmin,ss (extrapolated)
leaves the hospital room. Doses also can be missed if the patient
is absent from his or her room at the time medications are to be
SECTION

administered. If Css,old is much larger or smaller than expected for

the Dold the patient is taking, one should suspect noncompliance and 0.1
repeat the serum concentration determination after another three to 0 1 2 3 4 5 6 7 8 9 10
five half-lives or change the patient’s dose cautiously and monitor Time (h)
  

for signs of toxicity or lack of effect.

eFigure 5-10  When a patient has received enough doses to be
1 Measurement of Pharmacokinetic
at steady state, steady-state maximum (Cmax,ss) and minimum (Cmin,ss)
concentrations can be used to compute clearance, volume of
Parameters in Patients distribution, and half-life. At steady state, consecutive Cmin,ss values
Foundation Issues

are equal, so the predose value can be extrapolated to the time

15 If it is necessary to determine the kinetic constants for a patient
to individualize his or her dose, a small kinetic evaluation is con-
ducted in the individual. In these cases, the number of serum con-
centrations obtained from the patient is held to the minimum needed
to calculate accurate pharmacokinetic parameters and doses. The
reason for using fewer serum drug concentration determinations is
to be as cost-effective as possible because these laboratory tests gen-
erally cost $20 to $50 each.
Although many drugs follow two-compartment-model pharma-
cokinetics (especially after IV administration), a one-compartment
model is used to compute kinetic parameters in patients because too
many serum concentration determinations would be needed to deter-
mine accurately both the distribution and elimination phases found in
the two-compartment model. Because of this, serum concentrations
usually are not measured in patients during the distribution phase.
Another important reason serum concentrations are not measured
during the distribution phase for therapeutic drug-monitoring pur-
poses in patients is that drug in the blood and drug in the tissues are
not in equilibrium during this time, so that serum concentrations do
not reflect tissue concentrations. When drug serum concentrations are
obtained in patients for the purpose of assessing efficacy or toxicity, it
is important that they be measured in the postdistribution phase when
drug in the blood is in equilibrium with drug at the site of action.
In the case where the patient has received enough doses to be
at steady state, pharmacokinetic parameters can be computed using
a predose minimum concentration and a postdose maximum con-
centration. Under steady-state conditions, serum concentrations
after each dose are identical, so the predose minimum concentra-
tion is the same before each dose (eFig. 5-10). This situation allows
the predose concentration to be used to compute both the patient’s
t1/2 and V, where V = Dose/(Cmax,ss − Cmin,ss). If the drug was given
extravascularly or has a significant distribution phase, the postdose
before the next dose and used to calculate the half-life (dashed line).
could result in a concentration too low for the assay to detect. In this
situation, the predose minimum and postdose maximum concentra-
tions are used to compute V, where V = Dose/(Cmax − Cmin), and both
postdose concentrations are used to calculate t1/2 (eFig. 5-11).
After CL, V, and t1/2 have been computed for a patient, the dose
and dosage interval necessary to achieve desired steady-state serum
concentrations can be calculated using one-compartment-model
equations. Specific examples of these methods to calculate initial
doses and individualized doses using serum concentrations are dis-
cussed later in this chapter for the aminoglycoside antibiotics, van-
comycin, digoxin, theophylline, phenytoin, and cyclosporine.
Computer Programs
Computer programs that aid in the individualization of therapy are
available for many different drugs. The most sophisticated programs
use nonlinear regression to fit CL and VD to actual serum concen-
trations obtained in a patient.31 After drug doses and serum con-
centrations are entered into the computer, nonlinear least-squares
regression programs adjust CL and VD until the sum of the squared
error between actual (Cact) and computer-estimated concentrations
10
Cmax
t1/2
Concentration (mcg/mL)

concentration should be determined after absorption or distribution is

finished. To ensure that steady-state conditions have been achieved, C3
the patient needs to receive the drug on schedule for at least three to 1
Cmin
five estimated half-lives. To make sure that this is the case, inpatients
should have their medication administration records checked, and the
patient’s nurse should be consulted regarding missed or late doses.
Outpatients should be interviewed about compliance with the pre-
scribed dosage regimen. When compliance with the dosage regimen 0.1
0 1 2 3 4 5 6 7 8 9 10
has been verified, steady-state conditions reasonably can be assumed. Time (h)
If the patient is not at steady state, an additional postdose serum
concentration determination should be done to compute the patient’s eFigure 5-11  If a patient has not received enough doses to
pharmacokinetic parameters. Ideally, the third concentration (C3) be at steady state, or doses have been given on an irregular
should be acquired approximately one estimated half-life after the schedule, the minimum concentration (Cmin), maximum
postdose maximum concentration. Determining serum concentra- concentration (Cmax), and an additional postdose concentration
tions too close together will hamper the drug assay’s ability to mea- (C3) can be used to compute clearance, volume of distribution,
sure differences between them, and getting the third sample too late and half-life.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 63
(Cest) is at a minimum [Σ(Cest - Cact)2]. Once estimates of CL and VD intermittent IV infusion equation at steady state, and the dose is
are available, doses are calculated easily. rounded off to the nearest 5 to 10 mg:
Many programs also take into account what the CL and VD 1 – e–kτ
should be on the basis of disease states and conditions present in the D = TkVDCmax,ss
1 – e–kT
patient.32 Incorporation of expected population-based parameters
allows the computer to use a limited number of serum concentra- The Hull and Sarrubi aminoglycoside dosage nomogram
tions (one or two) to provide estimates of CL and VD. This type of (eTable 5-5) is based on this dosage-calculation method and includes
precalculated doses and dosage intervals for a variety of creatinine

computer program is called Bayesian because it incorporates por-
tions of Bayes’ theorem during the fitting routine.33 Bayesian phar-
macokinetic dosing programs are used widely to adjust the dose
of a variety of drugs. In the case of renally eliminated drugs (e.g.,
aminoglycosides, vancomycin, and digoxin), population estimates
for kinetic parameters are generated by entering the patient’s age,
weight, height, gender, and serum creatinine concentration into the
computer program. For hepatically eliminated drugs (e.g., theophyl-
line and phenytoin), population estimates for kinetic parameters are
computed using the patient’s age, weight, and gender, as well as other
e|CHAPTER  
clearance values.25 The nomogram assumes that VD = 0.26 L/kg and
should not be used to compute doses for disease states with altered VD.
An example of this initial dosage scheme for a typical case is
provided to illustrate the use of the various equations. Mr. JJ is a
eTable 5-5 Aminoglycoside Dosage Chart
1. Compute the patient’s creatinine clearance (CLcr) using the Cockcroft-
5
Gault method: CLcr = [(140 – age)BW]/(Scr × 72) where Scr is expressed

Clinical Pharmacokinetics and Pharmacodynamics

factors that might change hepatic clearance, such as the presence in units of mg/dL. Multiply by 0.85 for women. (Scr expressed in μmol/L
must be divided by 88.4 to obtain conventional units of mg/dL.)
or absence of disease states (e.g., cirrhosis or CHF) or other drug
2. Use the patient’s weight if within 30% of IBW; otherwise use adjusted
therapy that might cause a drug interaction. The p­ opulation-based body weight ABW = IBW + [0.40(TBW – IBW)] where IBW and TBW are
estimates of the pharmacokinetic parameters are then modified expressed in kg.
using nonlinear least-squares regression fits of serum concentrations 3. Select the loading dose in mg/kg to provide peak serum concentrations
to result in individualized parameters for the patient. The individual- in the range listed below for the desired aminoglycoside antibiotic:
ized parameters are used to compute doses for the patient that will Expected Peak Serum
result in desired steady-state concentrations of the drug. Aminoglycoside Usual Loading Doses Concentrations
Tobramycin 1.5–2 mg/kg 4–10 mcg/mL or mg/L
9 to 21 μmol/L
Aminoglycosides Gentamicin 1.5–2 mg/kg 4 to 10 mcg/mL or mg/L
Although aminoglycoside pharmacokinetics follow multicom- 8 to 21 μmol/L
partment models,34 a one-compartment model appears sufficient Netilmicin 1.5–2 mg/kg 4 to 10 mcg/mL or mg/L
to individualize doses in patients.35 Aminoglycosides usually are 8 to 21 μmol/L
given as short-term intermittent IV infusions and administered as Amikacin 5–7.5 mg/kg 15–30 mcg/mL or mg/L
a single daily dose or multiple doses per day. Initial doses for ami- 26 to 51 μmol/L
noglycosides can be computed using estimated kinetic parameters Kanamycin 5–7.5 mg/kg 15 to 30 mcg/mL or mg/L
31 to 62 μmol/L
derived from population pharmacokinetic data. The elimination
rate constant is estimated using the patient’s creatinine clearance 4. Select the maintenance dose (as a percentage of the loading dose)
to continue peak serum concentrations indicated above according to
in the following formula: k (in h−1) = 0.00293(CLcr) + 0.014, where the desired dosage interval and the patient’s creatinine clearance. To
CLcr is the measured or estimated creatinine clearance in millili- maintain the usual peak/trough ratio, use dosage intervals in clear areas.
ters per minute. The volume of distribution is estimated using the
Percentage of Loading Dose Required for Dosage Interval Selected
average population value for normal-weight (within 30% of ideal
Estimated
weight) individuals equal to 0.26 L/kg [V = 0.26(Wt), where Wt CLcr (mL/min)b Half-Life (h) 8 h (%) 12 h (%) 24 h (%)
is the patient’s weight] or for obese individuals (>30% of ideal
>90 2–3 90 — —
weight)36 by taking into account the patient’s excess adipose tis-
90 3.1 84 — —
sue: V = 0.26[IBW + 0.4(TBW - IBW)], where TBW is total body
80 3.4 80 91 —
weight, IBW is ideal body weight [IBWmales (in kilograms) = 50 +
70 3.9 76 88 —
2.3(Ht - 60) or IBWfemales (in kilograms) = 45 + 2.3(Ht - 60), and Ht
is the patient’s height in inches] (height in cm can be converted to 60 4.5 71 84 —
inches by multiplying by 0.394). Additional volume of distribution 50 5.3 65 79 —
population estimates are available for other disease states and condi- 40 6.5 57 72 92
tions, such as cystic fibrosis,37 ascites,38 and neonates.39 30 8.4 48 63 86
Appropriate Cmax,ss and Cmin,ss values are selected for the patient 25 9.9 43 57 81
based on the site and severity of the infection and the sensitivity of 20 11.9 37 50 75
the known or suspected pathogen, as well as avoidance of adverse 17 13.6 33 46 70
effects. Optimal outcomes are usually associated with Cmax,ss/MIC 15 15.1 31 42 67
ratios equal to 8 to 10, where MIC is the minimum inhibitory con- 12 17.9 27 37 61
centration for the bacteria causing the infection. For example, Cmax,ss 10a 20.4 24 34 56
values of 8 to 10 mg/L (8 to 10 mcg/mL) generally are selected for  7a 25.9 19 28 47
gram-negative pneumonia patients, whereas Cmin,ss values of less than  5a 31.5 16 23 41
2 mg/L (2 mcg/mL; 4 μmol/L) usually are chosen to avoid amino-  2a 46.8 11 16 30
glycoside-induced nephrotoxicity when tobramycin and gentamicin
 0a 69.3  8 11 21
are prescribed using conventional multiple-daily-dosing regimens.
Once appropriate steady-state serum concentrations are selected, the ABW, adjusted body weight; BW, body weight; IBW, ideal body weight; Scr, serum
creatinine; TBW, total body weight.
dosage interval required to achieve those concentrations is calcu- a
Dosing for patients with CLcr ≤10 mL/min should be assisted by measuring serum
lated, and τ is rounded to a clinically acceptable value (e.g., 8, 12, concentrations.
18, 24, 36, or 48 hours): τ = [(ln Cmax,ss - ln Cmin,ss)/k] + T. Finally, a b
CLcr expressed in mL/min can be converted to units of mL/s by dividing by 60.
dose is computed for the patient using the one-compartment-model Data from Reference 25.

Copyright © 2014 McGraw-Hill Education. All rights reserved.

 64
65-year-old, 80 kg (176 lb), 6-ft-tall (72 in. or 183 cm) man with
the diagnosis of gram-negative pneumonia. His serum creatinine
concentration is 2.1 mg/dL (186 μmol/L) and is stable. Compute
a conventional gentamicin dosage regimen (infused over 1 hour)
that would provide approximate peak and trough concentrations
of Cmax,ss = 8 mg/L (8 mcg/mL; 17 μmol/L) and Cmin,ss = 1.5 mg/L
(1.5 mcg/mL; 3.1 μmol/L), respectively. The patient is within 30%
of his ideal body weight [IBWmale = 50 + 2.3(72 in - 60) = 78 kg]
and has stable renal function, so the Cockcroft-Gault CLcr estimation
SECTION
equation can be used: CLcr est = [(140 - 65 y)80 kg]/[72(2.1 mg/dL)] =
40 mL/min (0.67 mL/s). The patient’s weight and estimated CLcr are
used to compute his V and k, respectively: V = 0.26 L/kg(80 kg) =
20.8  L; k  = 0.00293(40 mL/min) + 0.014 = 0.131  h−1 or t1/2 =
(0.693/0.131 h−1) = 5.3 h. The dosage interval and dose for the desired
1 serum concentrations would then be calculated: τ = [(ln 8 mg/L -
ln 1.5 mg/L)/0.131 h−1] + 1 h = 13.7 h rounded to 12 h; D = (1 h)
−1 −1
(0.131  h−1)(20.8 L)(8  mg/L) [1  - e−(0.131h (12h))/1 - e−(0.131h (1h))] =
Foundation Issues
140 mg. Thus, the prescribed dose would be gentamicin 140 mg every
12 hours administered as a 1-hour infusion. If a loading dose were
deemed necessary, it would be given as the first dose [LD = (20.8 L)
(8 mg/L) = 166 mg rounded to 170 mg infused over 1 hour], and the
first maintenance dose would be administered 12  hours (e.g., one
dosage interval) later. Using the Hull and Sarrubi nomogram for the
same patient, the loading dose is 160 mg (gentamicin loading dose
for serious gram-negative infection is 2 mg/kg: 2 mg/kg × 80 kg =
160 mg), and the maintenance dose is 115 mg every 12 hours (for a
12-hour dosage interval and CLcr est = 40 mL/min (0.65 mL/s), main-
tenance dose is 72% of the loading dose: 0.72 × 160 mg = 115 mg).
For extended-interval therapy, Cmax,ss values of 20 to 30 mg/L
(20 to 30 mcg/mL; 42 to 63 μmol/L) and Cmin,ss values less than
1 mg/L (1 mcg/mL; 2 μmol/L) generally are accepted as appropriate
for gram-negative pneumonia patients. A minimum 24-hour dosage
interval is chosen for this dosing technique, and the dosing inter-
val is increased in 12- to 24-hour increments for patients with renal
dysfunction.
An example of this initial dosage scheme for the same case is
provided to illustrate the use of extended-interval dosing. Mr. JJ is
65 years old, weighs 80 kg (176 lb). His height is 6 ft (72 in. [183 cm])
and his diagnosis is gram-negative pneumonia. His serum creatinine
concentration is 2.1 mg/dL (186 μmol/L) and is stable. Compute an
extended-interval gentamicin dosage regimen (infused over 1 hour)
that would provide approximate peak and trough concentrations of
Cmax,ss = 25 mg/L (25 mcg/mL; 52 μmol/L) and Cmin,ss = 0.5 mg/L
(0.5 mcg/mL; 1 μmol/L), respectively. The patient is within 30%
of his ideal body weight [IBWmale = 50 + 2.3(72 in - 60) = 78 kg]
and has stable renal function, so the Cockcroft-Gault CLcr estima-
tion equation can be used: CLcr est = [(140 - 65 y)80 kg]/[72(2.1 mg/
dL)] = 40 mL/min (0.67 mL/s). The patient’s weight and estimated
CLcr are used to compute his V and k, respectively: V = 0.26 L/
kg(80 kg) = 20.8 L; k = 0.00293(40 mL/min) + 0.014 = 0.131 h−1
or t1/2 = (0.693/0.131 h−1) = 5.3 h. The dosage interval and dose for
the desired serum concentrations would then be calculated: τ = [(ln
25 mg/L - ln 0.5 mg/L)/0.131 h−1] + 1 h = 31 h rounded to 36 h; D =
−1 −1
(1 h)(0.131 h−1)(20.8 L)(25 mg/L) [1 - e−(0.131h (36h))/1 - e−(0.131h (1h))] =
550 mg. Thus, the prescribed dose would be gentamicin 550 mg
every 36 hours administered as a 1-hour infusion.
Clinical Controversy. . .
Some clinicians use conventional dosing or extended-interval
dosing exclusively for patients requiring aminoglycosides,
whereas others use a mix of both approaches according to
the perceived benefit to the patient. Definitive, authoritative
recommendations to guide the choice of one method of
aminoglycoside dosing over the other are not available.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
If appropriate aminoglycoside serum concentrations are avail-
able, kinetic parameters can be calculated at any point in therapy.
When the patient is not at steady state, serum aminoglycoside con-
centrations are obtained before a dose (Cmin), after a dose admin-
istered as an IV infusion of ∼1 hour or as a 30-minute infusion
followed by a 30-minute waiting period to allow for drug distribu-
tion (Cmax), and at one additional postdose time (C3) approximately
one estimated half-life after Cmax. The t1/2 and k values are computed
using Cmax and C3: k = (ln Cmax - ln C3)/Δt and t1/2 = 0.693/k, where Δt
is the time that expired between the times Cmax and C3 were obtained.
If the patient is at steady state, serum aminoglycoside concentrations
are obtained before a dose (Cmin,ss) and after a dose administered as
an IV infusion of ∼1 hour or as a 30-minute infusion followed by
a 30-minute waiting period to allow for drug distribution (Cmax,ss).
Because the patient is at steady state, it can be assumed that Cmin,ss is
identical for each dosage interval. The t1/2 and k values are computed
using Cmax,ss and Cmin,ss: k = (ln Cmax,ss - ln Cmin,ss)/(τ - T) and t1/2 =
0.693/k, where τ is the dosage interval, and T is the dose infusion
time or dose infusion time plus waiting time.
Assuming a one-compartment model, the following equation is
used to compute VD:35
(D/T)(1 – e–kT)
VD =
k(Cmax – Cmine–kT)
where D is the dose, and T is the duration of infusion. Once these
are known, the dose and dosage interval (τ) can be calculated for any
desired maximum Css (Cmax,ss) and minimum Css (Cmin,ss):
ln Cmax,ss – ln Cmin,ss
τ = +T
k
1 – e–kτ
D = TkVDCmax,ss
1 – e–kT
The dose and dosage interval should be rounded to provide
clinically accepted values (every 8, 12, 18, 24, 36, and 48 hours for
dosage interval, nearest 5 to 10 mg for conventional dosing; every
24, 36, and 48 hours for dosage interval, nearest 10 to 25 mg for
extended interval dosing). This method also has been used to indi-
vidualize IV theophylline dosage regimens.40
To provide an example of this technique, the problem given
previously for conventional dosing will be extended to include
steady-state concentrations. Please note that this method of dos-
age adjustment using serum concentrations can also be used for
extended-interval dosing. Mr. JJ was prescribed gentamicin 140 mg
every 12 hours (infused over 1 hour) for the treatment of gram-neg-
ative pneumonia. Steady-state trough (Cmin,ss) and peak (Cmax,ss) val-
ues were obtained before and after the fourth dose was given (more
than three to five estimated half-lives), respectively, and equaled
Cmin,ss = 2.8 mg/L (2.8 mcg/mL; 5.9 μmol/L) and Cmax,ss = 8.5 mg/L
(8.5  mcg/mL; 18 μmol/L). Clinically, the patient was improving
with decreased white blood cell counts and body temperatures and
a resolving chest radiograph. However, the serum creatinine value
had increased to 2.5 mg/dL (221 μmol/L). Because of this, a new
dosage regimen with a similar peak (to maintain high intrapulmo-
nary levels) but lower trough (to decrease the risk of drug-induced
nephrotoxicity) concentrations was suggested. The patient’s elimi-
nation rate constant and half-life can be computed using the fol-
lowing formulas: k = (ln 8.5 mg/L - ln 2.8 mg/L)/(12 h - 1 h) =
0.101 h−1 and t1/2 = 0.693/0.101 h−1 = 6.9 h. The patient’s volume of
distribution can be calculated using the following equation:
(140 mg/l h) 1 − e–(0.101 h–1)(1 h)
V= = 22.3 L
(0.101 h–1) 8.5 mg/L − (2.8 mg/L)e–(0.101 h–1)(1 h)
 65
Thus, the patient’s volume of distribution was larger and half-
life was longer than originally estimated; this led to higher serum 14
concentrations than anticipated. To achieve the desired serum con- 13
centrations (Cmin,ss = 1.5 mg/L [1.5 mcg/mL; 3.1 μmol/L] and Cmax,ss = 12
8 mg/L [8.0 mcg/mL; 17 μmol/L]), the patient’s actual kinetic param- 11

Concentration (mcg/mL)
eters are used to compute a new dose and dosage interval: τ = [(ln 10
8 mg/L - ln 1.5 mg/L)/0.101 h−1] + 1 h = 17.6 h, rounded to 18 h and 9
q 48 h

e|CHAPTER  
8

1 – e–(0.101 h–1)(18 h)
 7

D = (1 h)(0.101 h–1)(8 mg/L) 6 q 36 h

1 – e–(0.101 h–1)(1 h)

5

4 q 24 h
= 157 mg, round to 160 mg
3
Thus, the new dose would be gentamicin 160 mg every 18 2
hours and infused over 1 hour; the first dose of the new dosage regi-
men would be given 18 hours (e.g., the new dosage interval) after
6 7 8 9 10 11 12 13
Time between start of infusion and sample draw (h)
14
5
the last dose of the old dosage regimen. 1. Administer 7 mg/kg gentamicin or tobramycin with initial dosage

Clinical Pharmacokinetics and Pharmacodynamics

Because aminoglycoside antibiotics exhibit concentration-
dependent bacterial killing, and the postantibiotic effect is longer
with higher concentrations, investigators studied the possibility of
giving a higher dose of aminoglycoside using an extended-dosage
interval (24 hours or longer, depending on renal function). Generally,
these studies have shown comparable microbiologic and clinical cure
rates for many infections and about the same rate of nephrotoxicity
(∼5-10%) as with conventional dosing. Ototoxicity has not been
monitored using audiometry in most of these investigations, but loss
of hearing in the conversational range, as well as signs and symp-
toms of vestibular toxicity, usually has been assessed and found to
be similar to that with aminoglycoside therapy dosed conventionally.
Based on these data, clinicians are using extended-interval dosing in
selected patients. For Pseudomonas aeruginosa infections where the
organism has an expected minimum inhibitory concentration (MIC)
≈ 2 mg/L, peak concentrations between 20 and 30 mg/L (20 and
30 mcg/mL) and trough concentrations less than 1 mg/L (1 mcg/mL;
2 μmol/L) for gentamicin or tobramycin have been suggested.41
At the present time, there is no consensus on how to approach
concentration monitoring using this mode of administration. Some
clinicians obtain steady-state peak and trough concentrations and
use the kinetic equations given earlier to adjust the dose and dosage
interval in order to attain appropriate target levels. Other clinicians
measure only trough concentrations, trusting that the large doses
administered to patients achieve adequate peak concentrations.
Also, a nomogram that adjusts extended-interval doses based
on a single postdose concentration to achieve these Css goals has
been proposed (eFig. 5-12). The dose is 7 mg/kg of gentamicin
or tobramycin. The initial dosage interval is set according to the
patient’s CLcr. The Hartford nomogram includes a method to adjust
doses based on serum concentrations. This portion of the nomogram
contains average serum concentration time lines for gentamicin or
tobramycin in patients with creatinine clearances of 60, 40, and
20 mL/min (1, 0.67, 0.33 mL/s, respectively). A serum concentra-
tion is measured 6 to 14 hours after the first dose is given, and this
concentration/time point is plotted on the graph (see eFig. 5-12).
The modified dosage interval is indicated by which zone the serum
concentration/time point falls. Because cystic fibrosis patients have
a different volume of distribution (0.35 L/kg) than assumed by this
dosing technique, and extended-interval dosing has not been tested
adequately in patients with endocarditis, the Hartford nomogram
should not be used in these situations.
To illustrate how the Hartford nomogram is used, the same
patient example used previously will be repeated for this dos-
age approach. Mr. JJ weighs 80 kg (176 lb) and has a CLcr est of
40 mL/min (0.67 mL/s). Using the Hartford nomogram, the patient
would receive gentamicin 560 mg every 36 hours (7 mg/kg ×
80 kg = 560 mg; the initial dosage interval for CLcr est = 40 mL/min
[0.67 mL/s] is 36 hours). Ten hours after the first dose was given, the
Copyright © 2014 McGraw-Hill Education. All rights reserved.
interval:
Estimated CLcr (mL/min) Initial dosage interval
≥60 mL/min q 24 h
40–59 mL/min q 36 h
20–39 mL/min q 48 h
<20 mL/min Monitor serial concentrations
and administer next dose when
<1 mcg/mL
2. Obtain timed serum concentration 6 to 14 hours after dose
(ideally first dose)
3. Alter dosage interval to that indicated by the nomogram
zone (above q 48 h zone, monitor serial concentrations
and administer next dose when <1 mcg/mL)
eFigure 5-12  Hartford nomogram for extended-interval
aminoglycosides. (From Reference 41. Reproduced with permission
from American Society for Microbiology.) To determine the
corresponding creatinine clearance in units of mL/s divide the
value in mL/min by 60. Gentamicin levels in mcg/mL can be
converted to units of μmol/L by multiplying by 2.09.
serum gentamicin concentration is 8.2 mg/L (17 μmol/L). According
to the graph contained in the nomogram, the dosage interval should
be changed to 48 hours. The new dose is 560 mg every 48 hours.
Clinical Controversy. . .
“Trough only” measurement of steady-state vancomycin
concentrations is a mainstream method to monitor
therapy. The exact range for this value is uncertain. Many
clinicians recommend 5 to 15 mcg/mL (5 to 15 mg/L;
3.45 to 10 μmol/L). For some sites of infection with specific
organisms, such as hospital-acquired pneumonia caused
by multidrug-resistant organisms, guidelines suggest
vancomycin trough concentrations as high as 15 to 20 mcg/
mL (15 to 20 mg/L; 10 to 14 μmol/L) may be necessary. Some
clinicians continue to measure both steady-state peak and
trough vancomycin concentrations. Optimal outcomes are
usually associated with AUC24/MIC ratios greater than 400,
where MIC is the minimum inhibitory concentration for the
causative organism.
 66
Vancomycin
Vancomycin requires multicompartment models to completely
describe its serum-concentration-versus-time curves. However, if
peak serum concentrations are obtained after the distribution phase
is completed (usually 30 minutes to 1 hour after a 1-hour IV infu-
sion), a one-compartment model can be used for patient dosage
calculations. Also, because vancomycin has a relatively long half-
life compared with the infusion time, only a small amount of drug
SECTION
is eliminated during infusion, and it is usually unnecessary to use
more complex IV infusion equations. Thus, simple IV bolus equa-
tions can be used to calculate vancomycin doses for most patients.
Although a recent review article42 questioned the clinical usefulness
of measuring vancomycin concentrations on a routine basis, other
1 research articles44,45 have shown potential benefits in obtaining van-
comycin concentrations in select patient populations. Some clini-
cians advocate monitoring only steady-state trough concentrations
of vancomycin.46 The decision to conduct vancomycin concentra-
Foundation Issues
tion monitoring should be made on a patient-by-patient basis.
Initial doses of vancomycin can be computed for adult patients
using estimated kinetic parameters derived from population phar-
macokinetic data. Clearance is estimated using the patient’s cre-
atinine clearance in the following equation:43 CL (in mL/min/kg)
= 0.695(CLcr in mL/min/kg) + 0.05. The volume of distribution is
computed assuming the standard value of 0.7 L/kg: VD = 0.7(Wt),
where Wt is the patient’s weight. In the case of obese patients, actual
or total body weight is used in the calculation of clearance, but ideal
body weight is used to compute volume of distribution.47 The elim-
ination rate constant is calculated using clearance and volume of
distribution estimates, correcting for possible differences in units
for these parameters: k = CL/VD. A nomogram that uses this type of
approach for vancomycin therapy is available to determine initial
doses rapidly for patients (eTable 5-6).24
Steady-state peak and trough concentrations are chosen for the
patient based on the site and severity of the infection, as well as
the known or suspected pathogen and avoidance of potential side
eTable 5-6 Vancomycin Dosage Chart
1. Compute patient’s creatinine clearance (CLcr) using the Cockcroft-Gault
method: CLcr = [(140 – age)BW]/(SCr × 72), where Scr is expressed in units
of mg/dL. Multiply by 0.85 for women. (Scr expressed in μmol/L must be
divided by 88.4 to obtain conventional units of mg/dL.)
2. Use the patient’s TBW to compute doses.
3. Dosage chart designed to achieve peak serum concentrations of
30 mcg/mL (30 mg/L; 21 μmol/L) and trough concentrations of
7.5 mcg/mL (7.5 mg/L; 5 μmol/L).
4. Compute loading dose of 25 mg/kg.
5. Compute maintenance dose of 19 mg/kg given at the dosage interval
listed in the following chart for the patient’s CLcr:
CLcr (mL/min)a Dosage Interval (Days)
≥120 0.5
 100 0.6
  80 0.75
  60 1.0
  40 1.5
  30 2.0
  20 2.5
  10 4.0
   5 6.0
   0 12.0
BW, body weight; Scr, serum creatinine; TBW = total body weight.
Clcr expressed in mL/min can be converted to units of mL/s by dividing by 60.
a
Data from Reference 24.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
effects. Optimal outcomes are usually associated with AUC24/MIC
ratios greater than 400, where AUC24 is the area under the vancomy-
cin concentration/time curve for 24 hours and MIC is the minimum
inhibitory concentration for the bacteria causing the infection. Cmax,ss
values of between 20 and 40 mg/L (20 and 40  mcg/mL; 14 and
28 μmol/L) and Cmin,ss values of between 5 and 15  mg/L (5 and
15 mcg/mL; 3 and 10 μmol/L) typically are used for patients with
mild to moderate infections or sensitive bacteria with lower MIC
values (<1 mcg/mL). For patients with pneumonia or other life-­
threatening infections due to multidrug-resistant organisms, Cmin,ss
as high as 15–20 mg/L (15–20 mcg/mL; 10–14 μmol/L) have been
suggested.48 After appropriate steady-state concentrations are cho-
sen, the dosage interval required to attain those concentrations is
computed, and τ is rounded to a clinically acceptable value (8, 12,
18, 24, 36, 48, or 72 hours): τ = (ln Cmax,ss - ln Cmin,ss)/k. Finally,
the maintenance dose is computed for the patient using a one-­
compartment-model IV bolus equation at steady state, and the dose
is rounded off to the nearest 100 to 250 mg:
D = Cmax,ss VD (1 - e-kt)
If desired, a loading dose can be computed using the following
equation:
LD = VD Cmax,ss
The following case will illustrate the use of this dosage meth-
odology. Ms. HJ is 65 years old, weighs 68 kg (150 lb), and is 5 ft
4  in. (64 in. [163 cm]) tall. She has developed a surgical wound
infection; S. epidermidis is the suspected pathogen. Her serum cre-
atinine concentration is 1.8 mg/dL (159 μmol/L) and stable. Com-
pute a vancomycin dosage regimen that would provide approximate
peak (obtained 1 hour after a 1-hour infusion) and trough concen-
trations of 30 and 7 mg/L (30 and 7 mcg/mL; 21 and 5 μmol/L),
respectively. The patient is within 30% of her ideal body weight
[IBWfemale = 45 + 2.3(64 in. - 60) = 54 kg] and has stable renal
function, so the Cockcroft-Gault creatinine clearance estimation
formula can be used: CLcr est = 0.85[(140 - 65 y)68 kg]/[72(1.8 mg/
dL)] = 33 mL/min (0.55 mL/s). The patient’s weight and CLcr est are
used to calculate her estimated CL, VD, and k, respectively: CL =
0.695 (33 mL/min/68 kg) + 0.05 = 0.387 mL/min/kg; VD = 0.7 L/kg
(68 kg) = 48 L; and k = [(0.387 mL/min/kg)(68 kg)(60 min/h)]/
[(48 L)(1,000 mL/L)] = 0.033 h−1 or t1/2 = 0.693/0.033 h−1 = 21 h.
The dosage interval, maintenance dose, and loading dose for the
desired serum concentrations can be computed: τ = (ln 30 mg/L -
ln 7 mg/L)/0.033 h−1 = 44 h, rounded to 48 h; D = (30 mg/L) (48 L)
(1 - e−(0.033h−1)(48h)) = 1,145 mg, rounded to 1,250 mg; LD = (48 L)
(30  mg/L) = 1,440 mg, rounded to 1,500 mg. Therefore, the pre-
scribed dose would be vancomycin 1,250 mg every 48 hours admin-
istered as a 1-hour infusion. If a loading dose was used, it would
be given as the first dose, and the first maintenance dose would
be administered 48 hours (one dosage interval) later. Using the
Matzke nomogram for the same patient, the loading dose would
be 1,750  mg (vancomycin loading dose is 25 mg/kg: 25 mg/kg ×
68  kg = 1,700  mg, rounded to 1,750 mg), followed by a mainte-
nance dose of 1,250 mg every 48 hours (for CLcr  est = 30 mL/min
(0.50  mL/s)), the maintenance dose is 19 mg/kg every 2 days:
19 mg/kg × 68 kg = 1,292 mg, rounded to 1,250 mg).
If appropriate vancomycin serum concentrations are available,
kinetic parameters can be computed at any point in therapy. When
the patient is not at steady state, serum vancomycin concentrations
are obtained before a dose (Cmin), after a dose administered as an IV
infusion of 1 hour followed by a 30-minute to 1-hour waiting period
to allow for drug distribution (Cmax), and at one additional postdose
time (C3) approximately one estimated half-life after Cmax. The t1/2
and k values are computed using Cmax and C3: k = (ln Cmax - ln C3)/Δt
and t1/2 = 0.693/k, where Δt is the time that expired between the times
Cmax and C3 were obtained. If the patient is at steady state, serum

vancomycin concentrations are obtained before a dose (Cmin,ss) and
after a dose administered as an IV infusion of approximately 1 hour
followed by a 30-minute to 1-hour waiting period to allow for drug
distribution (Cmax,ss). The t1/2 and k values are computed using Cmax,ss
and Cmin,ss: k = (ln Cmax,ss - ln Cmin,ss)/(τ - Tmax) and t1/2 = 0.693/k,
where τ is the dosage interval, and Tmax is the dose infusion time
plus waiting time.
Assuming a one-compartment model, the following equation is
used to compute VD:
D 100 mcg/mL; 55 to 69 μmol/L]) are quite a bit higher than therapeu-
VD =
Cmax – Cmin
where D is dose. Once these are known, the dose and dosage inter-
val (τ) can be calculated for any desired maximum Css(Cmax,ss) and
minimum Css(Cmin,ss):
ln Cmax,ss – ln Cmin,ss
τ=
k tive45 and prospective45 studies. Trough concentrations in the range
D = Cmax,ssVD (1 – e–kτ )
The dose and dosage interval should be rounded to provide
clinically accepted values (every 8, 12, 18, 24, 36, 48, or 72 hours
for dosage interval, nearest 100 to 250 mg for dose).
To provide an example for this dosage-calculation method, the
preceding problem will be extended to include steady-state con-
centrations. Ms. HJ was prescribed vancomycin 1,200 mg every
48 hours (infused over 1 hour) for the treatment of a surgical wound
infection. Steady-state trough (Cmin,ss) and peak (Cmax,ss) values
(Cmax,ss obtained 1 hour after the end of the infusion) were obtained
before and after the third dose was given (more than three to five
estimated half-lives), respectively, and equaled Cmin,ss = 2.5 mg/L
(2.5 mcg/mL; 1.7 μmol/L) and Cmax,ss = 22.4 mg/L (22.4 mcg/mL;
15.5 μmol/L). Clinically, the patient had improved somewhat, but
her white blood cell count was still elevated, and the patient was still
febrile. Because of this, a modified dosage regimen with a Cmax,ss =
30 mg/L (30 mcg/mL; 21 μmol/L) and Cmin,ss = 7 mg/L (7 mcg/mL;
5 μmol/L) was suggested to maintain an AUC24/MIC ratio greater
than 400. The patient’s actual elimination rate constant and half-life
can be calculated using the following formulas: k = (ln 22.4 mg/L
- ln 2.5 mg/L)/(48 h - 2 h) = 0.048 h−1 and t1/2 = 0.693/0.048 h−1 =
14.4 h. The patient’s volume of distribution can be calculated using
the following equation:
1,200 mg
VD = = 60 L
22.4 mg/L – 2.5 mg/L
Thus, the patient’s volume of distribution was larger and
half-life shorter than originally estimated; this led to lower serum
concentrations than anticipated. To achieve the desired serum con-
centrations (Cmax,ss = 30 mg/L [30 mcg/mL; 21 μmol/L] and Cmin,ss =
7 mg/L [7 mcg/mL; 5 μmol/L]), the patient’s actual kinetic param-
eters are used to calculate a new dose and dosage interval:
ln 30 mg/L – ln 7 mg/L
τ=
0.048 h –1
= 30 h, rounded to 36 h
 
D = (30 mg/L)(60 L) 1 – e–(0.048 h–1)(36 h)
= 1,480 mg, rounded to 1,500 mg
The new dose would be vancomycin 1,500 mg every 36 hours
(infused over 1 hour); the first dose of the new dosage regimen
would be given 36 hours (the new dosage interval) after the last dose
of the old dosage regimen.
For routine monitoring, many clinicians measure only steady-
state vancomycin trough concentrations in patients. The justification
for this approach is that because vancomycin exhibits time-dependent
Copyright © 2014 McGraw-Hill Education. All rights reserved.
67
bacterial killing, the minimum concentration is the most important
with regard to therapeutic outcome. Vancomycin pharmacokinet-
ics also support this approach because the volume of distribution is
relatively stable and is not changed by many disease states or condi-
tions. Because of this important point, it is difficult to attain peak
steady-state concentrations in the toxic range when the steady-state
vancomycin trough is in the therapeutic range if typical doses are
e|CHAPTER  
used (15 mg/kg or ≈ 1,000 mg for average-weight individuals). Also,
toxic peak concentrations (generally greater than 80–100 mg/L [80 to
tic peak concentrations, which adds a safety margin between effective
concentrations and those yielding adverse drug effects.
Coupled with trough-only vancomycin concentration monitor-
ing is a widening of the therapeutic steady-state trough concentra-
tion range from 5 to 15 mg/L (5 to 15 mcg/mL; 3 to 10 μmol/L). The
justification for increasing the top of the range from 10 to 15 mg/L
5
(10 to 15 mcg/mL; 7 to 10 μmol/L) comes from limited retrospec-
Clinical Pharmacokinetics and Pharmacodynamics
of 15 to 20 mg/L (15 to 20 mcg/mL; 10 to 14 μmol/L) should be
reserved for specific clinical situations, such as hospital-acquired
pneumonia or other severe infections caused by multidrug-resistant
organisms.48 As previously mentioned, optimal outcomes are usu-
ally associated with AUC24/MIC ratios greater than 400, where MIC
is the minimum inhibitory concentration for the causative organism.
When trough-only monitoring of vancomycin concentrations
is chosen by a clinician, a simple variant of linear pharmacokinetics
can be used to adjust the dose (D) and dosage interval (τ): (Dnew/
τnew) = (Dold/τold)(Css,new/Css,old), where new and old indicate the new
target trough concentration and the old measured trough concentra-
tion, respectively. In practice, the dose (typically 1,000–1,500 mg)
is often held constant, and only the dosage interval is changed. This
equation is an approximation of the actual new steady-state trough
concentration that will be attained in the patient because, mathemat-
ically, Css,new is an exponential function of τ.
An example of this approach is given in the following case.
Mr. MK is 72 years old, weighs 72 kg (158 lb), and measures 5 ft
9 in. (69 in. [175 cm]). He was prescribed vancomycin 1,000 mg
every 12 hours (infused over 1 hour) for the treatment of an S. epi-
dermidis central venous catheter infection. A steady-state trough
(Cmin,ss) value was obtained before the fifth dose was given (more than
three to five estimated half-lives), and Cmin,ss = 19 mg/L (19 mcg/mL;
13  μmol/L). Clinically, the patient was improving, but the trough
concentration was judged to be too high. Because of this, a modified
dosage regimen with a Cmin,ss = 10 mg/L (10 mcg/mL; 7 μmol/L) was
suggested to maintain an AUC24/MIC ratio greater than 400. (Dnew/
τnew) = (1,000 mg/12 h)(10 mg/L/19 mg/L) = 44 mg/h. Because the
patient is near his ideal weight, the same dose of 1,000 mg can be
used (Dnew), and the new dosage interval (τnew) can be computed:
τ = 1,000 mg/44 mg/h = 23 h, rounded to 24 h. The new prescribed
dose for the patient would be 1,000 mg every 24 hours.
Digoxin
Digoxin pharmacokinetics are best described by a two-compartment
model. However, because digoxin has a long half-life compared
with its dosage interval and a very long distribution phase, simple
pharmacokinetic equations can be used to individualize dosing
when postdistribution serum concentrations are used. Digoxin can
be given as an IV injection and orally as elixir (F = 0.8) or tablets
(F = 0.7). When given orally, the appropriate bioavailability fraction
must be used to compute the correct dose. Initial doses of digoxin
can be computed using population pharmacokinetic data obtained
from published studies. Digoxin clearance is estimated using the
patient’s CLcr in the following formula:23 CL (in milliliters per min-
ute) = 1.303(CLcr in milliliters per minute)  + CLm, where CLm is
metabolic clearance and equals 40 mL/min for patients with no or
 68
mild heart failure or 20 mL/min for patients with moderate to severe
heart failure. The volume of distribution decreases with declining
renal function and is estimated using the following equation:23 VD
(in liters) = 226 + [298(CLcr in milliliters per minute)]/(29.1 + CLcr
in milliliters per minute). The elimination rate constant can be com-
puted by taking the product of CL and VD: k = CL/VD. For obese
individuals, digoxin dosing should be based on ideal body weight.49
Appropriate Css values are chosen for the patient based on the
disease state being treated, the goal of therapy, and avoidance of
SECTION
adverse effects. The inotropic effects of digoxin occur at lower con-
centrations than do the chronotropic effects. Therefore, initial serum
concentrations of digoxin for the treatment of heart failure generally
are 1 ng/mL (1 mcg/L; 1.3 nmol/L) or less and for the treatment of
atrial fibrillation 1 to 1.5 ng/mL (1 to 1.5 mcg/L; 1.3 to 1.9 nmol/L).
1 Once the appropriate Css is selected, a dose is computed for the
patient: D/τ = (CssCL)/F.
An example of this initial dosage scheme is provided in the fol-
Foundation Issues
lowing case. Mr. PO is 72 years old, weighs 83 kg (183 lb), and mea-
sures 5 ft 11 in. (71 in. [180 cm]). He was admitted to the hospital
for the treatment of community-acquired pneumonia. His past medi-
cal history is positive for moderate heart failure. While in the hos-
pital, Mr. PO develops atrial fibrillation, and the decision is made to
treat him with digoxin to provide ventricular rate control. His serum
creatinine concentration is 2.5 mg/dL (221 μmol/L) and stable.
Calculate an IV loading dose and oral maintenance dose that will
achieve a Css of 1.5 ng/mL (1.5 mcg/L; 1.9 nmol/L). The Cockcroft-
Gault equation can be used to estimate the patient’s CLcr because
his serum creatinine concentration is stable, and he is within 30% of
his ideal body weight [IBWmale = 50 + 2.3(71 in - 60) = 75 kg]: CLcr
= [(140 - 72 y)83 kg]/[72(2.5 mg/dL)] = 31 mL/min (0.52 mL/s).
Using the estimated CLcr, both CL and VD can be computed:
CL = 1.303(31 mL/min) + 20 = 60 mL/min
298(31 mL/min)
VD = 226 + = 380 L
29.1 + 31 mL/min
The maintenance dose will be given as digoxin tablets, so
F  = 0.7 in the dosing equation: D/τ = [(1.5 mcg/L)(60 mL/min)
(60 min/h)(24 h/day)]/[0.7(1,000 mL/L)] = 185 mcg/day, rounded to
187.5 mcg/day (given as 1½ of 125 mcg tablets). The loading dose
will be given IV as a digoxin injection: LD = (1.5 mcg/L)(380 L)
= 570 mcg, rounded to 500 mcg. The loading dose would be given
50% now (250 mcg), 25% (125 mcg) in 4 to 6 hours after moni-
toring the patient’s heart rate and blood pressure and assessing the
patient for digoxin adverse effects, and the final 25% (125 mcg) 4 to
6 hours later after monitoring the same clinical parameters. The first
maintenance dose would be given one dosage interval (in this case,
24 hours) after the first part of the loading dose was given.
Adjustment of digoxin doses using steady-state concentrations
is accomplished using linear pharmacokinetics and dosage ratios:
Dnew = Dold(Css,new/Css,old). For example, Mr. PO’s atrial fibrillation
responded to digoxin therapy, and he was discharged after resolution
of his pneumonia. A month later, he was followed up in the clinic with
moderate nausea, possibly a result of digoxin toxicity. His heart rate
was 51 beats per minute, and his serum creatinine was unchanged. A
steady-state digoxin concentration was determined and reported by
the clinical laboratory as 2.2 mcg/L (2.8 nmol/L). Compute a new dose
for the patient to achieve a Css of 1.5 mcg/L (1.9 nmol/L). The digoxin
Css and old dose would be used to calculate a new dose using the
linear pharmacokinetic equation: Dnew = 187.5 mcg/day[(1.5 mcg/L)/
(2.2 mcg/L)] = 128 mcg/day, rounded to 125 mcg/day.
Theophylline
Theophylline disposition is described most accurately by nonlinear
kinetics.50,51 However, at the usual doses, theophylline acts as if it
obeys linear kinetics in most patients. Initial theophylline doses are
Copyright © 2014 McGraw-Hill Education. All rights reserved.
computed by taking a detailed medical history of the patient and
noting disease states and conditions that are known to change the-
ophylline disposition. Age, smoking of tobacco-containing prod-
ucts, heart failure, and liver disease are among the important factors
that alter theophylline kinetic parameters and dosage requirements.
Once the patient has been assessed, average theophylline kinetic
parameters obtained from the literature for patients similar to the
one being currently treated are used to compute either oral or IV
doses. Dosage guidelines that take into account most common
disease states and conditions that change theophylline kinetic
parameters are available (see eTable 5-4).52 Once theophylline is
administered, the patient is monitored for the therapeutic effect and
potential adverse effects. Theophylline concentrations then are used
to individualize the theophylline dose that the patient receives. An
example of this approach was given previously for a patient in the
section on drug dosing in patients with liver disease (see Selection
of Initial Drug Doses above).
Continuous IV infusions of theophylline (or its salt, amino-
phylline) can be individualized rapidly by determining the patient’s
CL before steady state occurs.53 Assuming that the patient receives
theophylline only by continuous IV infusion (previous doses of
sustained-release oral theophylline are completely absorbed), two
serum theophylline concentration determinations are done 4 hours
or more apart. The infusion rate (k0) cannot be changed between the
times the samples are drawn. With one-compartment model equa-
tions, the first (C1) and second (C2) theophylline concentrations are
used to calculate theophylline CL:
2k0 2VD(C1 – C2)
CL = +
C1 + C2 (C1 + C2)(t2 – t1)
VD is assumed to be 0.5 L/kg, and t1 and t2 are the times at
which C1 and C2, respectively, are obtained. Once CL is known,
k0 can be computed easily for any desired Css (Css = k0/CL). This
method probably can be applied to other drugs that are administered
as continuous IV infusions, such as IV antiarrhythmics, when rapid
individualization of drug dosage is desirable.
An example of this approach can be obtained by continuing the
theophylline patient case from the section on drug dosing in liver
disease (see Selection of Initial Drug Doses above). In this example,
a 55-year-old, 70 kg (154 lb) man with liver cirrhosis was prescribed
a loading dose of theophylline 350 mg IV over 20 to 30 minutes, fol-
lowed by a maintenance dose of 15 mg/h of theophylline as a con-
tinuous infusion. The infusion began at 9 am, blood samples were
obtained at 10 am and 4 pm, and the clinical laboratory reported the
theophylline serum concentrations as 10.9 and 12.3 mg/L (10.9 and
12.3 mcg/mL; 60.5 and 68.3 μmol/L), respectively. The patient’s
theophylline clearance and revised continuous infusion to maintain
a Css of 15 mg/L (15 mcg/mL; 83.3 μmol/L) can be computed as
follows (patient’s VD estimated at 0.5 L/kg):
2(15 mg/h)
CL =
10.9 mg/L + 12.3 mg/L
2(0.5 L/kg × 70 kg)(10.9 mg/L – 12.3 mg/L)
+ = 0.59 L/h
(10.9 mg/L + 12.3 mg/L)(16 – 10 h)
k0 = CssCL = (15 mg/L)(0.59 L/h) = 9 mg/h theophylline
If theophylline is to be given as the aminophylline salt form,
the doses would need to be changed to reflect the fact that amino-
phylline contains only 85% theophylline (k0 = 9 mg/h theophylline/
0.85 = 11 mg/h aminophylline).
If continuous IV infusions or oral dosage regimens are given
long enough for steady state to occur (three to five estimated half-
lives based on previous studies conducted in similar patients), lin-
ear pharmacokinetics can be used to adjust doses for either route
of administration: Dnew = Dold(Css,new/Css,old). For example, a patient

receiving 200 mg of sustained-release oral theophylline every
12  hours with a theophylline steady-state serum concentration of
9.5 mcg/mL (9.5 mg/L; 52.7 μmol/L) can have the dose required to
achieve a new Css equal to 15 mcg/mL (15 mg/L; 83.3 μmol/L) com-
puted by applying linear pharmacokinetics: Dnew = 200 mg[(15 mcg/
mL)/(9.5 mcg/mL)] = 316 mg, rounded to 300 mg. Thus the new
theophylline dose would be 300 mg every 12 hours.
Phenytoin
Phenytoin doses are very difficult to individualize because the drug
follows Michaelis-Menten kinetics, and there is a large amount of
interpatient variability in Vmax and Km. Initial maintenance doses
of phenytoin in adults usually range between 4 and 7 mg/kg daily,
yielding starting doses of 300 to 400 mg daily in most individuals.
If needed, loading doses of phenytoin or fosphenytoin (a prodrug
of phenytoin used IV) can be administered in adults at a dose of
15 mg/kg, which is approximately 1,000 mg in many individu-
als. Loading doses of phenytoin can be given orally but need to be
administered in divided doses separated by several hours in order to
avoid decreased bioavailability and gastrointestinal intolerance (for
total loading dose of 1,000 mg: 400 mg, 300 mg, then 300 mg with
each dose separated by 4 to 6 h). Because phenytoin is metabolized
hepatically, decreased doses may be needed in patients with liver
disease. Because phenytoin follows dose-dependent pharmacokinet-
ics, the half-life of phenytoin increases for a patient as the mainte-
nance dose increases. Therefore, the time to steady-state phenytoin
concentrations increases with dose. On average, at a phenytoin dose
of 300 mg daily, it takes approximately 5 to 7 days to achieve steady
state; at a dose of 400 mg daily, it takes approximately 10 to 14 days
to achieve steady state; and at a dose of 500 mg daily, it takes approx-
imately 21 to 28 days to achieve steady state. It should be noted that
the injectable and capsule dosage forms of phenytoin are phenytoin
sodium, and the labeled dosage amounts contain 92% of active
phenytoin (300 mg phenytoin sodium capsules contain 276  mg
[300 mg × 0.92 = 276 mg] of active phenytoin). Unbound phenytoin
concentrations are useful in patients with hypoalbuminemia (e.g.,
liver disease, nephrotic syndrome, pregnancy, cystic fibrosis, burns,
trauma, and malnourishment, as well as in the elderly), in patients in
whom displacement with endogenous compounds is possible (e.g.,
hyperbilirubinemia, liver disease, or end-stage renal disease), and
in patients receiving other drugs that may displace phenytoin from
plasma protein-binding sights (e.g., valproic acid, aspirin therapy
>2 g daily, warfarin, and nonsteroidal antiinflammatory drugs with
high albumin binding).54
After steady state has occurred, phenytoin serum concentra-
tions can be obtained as an aid to dosage adjustment. A simple, easy
way to approximate new serum concentrations after a dosage adjust-
ment with phenytoin is to temporarily assume linear pharmacoki-
netics and then add 15% to 33% for a dosage increase or subtract
15% to 33% for a dosage decrease to account for Michaelis-Menten
kinetics. To avoid large disproportionate changes in phenytoin con-
centrations when using this empirical method, dosage adjustments
should be limited to 50 to 100 mg daily. This technique is intended
only to provide a rough approximation of the resulting phenytoin Css
after an appropriate dosage adjustment has been made.
For example, Ms. PP is a 35-year-old, 65 kg (143 lb) patient
with grand mal seizures who is receiving phenytoin capsules 300 mg
orally at bedtime. A Css of 9.2 mcg/mL (9.2 mg/L; 37 μmol/L) is
measured. It is observed that her seizure frequency decreased by
only ∼15%, and that she has had no adverse effects as a conse-
quence of phenytoin treatment. Because of this, her phenytoin dose
is increased to 400 mg orally at bedtime. The expected phenytoin Css
would be estimated using linear pharmacokinetics [Cnew = (Dnew/Dold)
Cold = (400 mg/300 mg)/(9.2 mcg/mL) = 12.3 mcg/mL] and then
increased by 15% to 33% to account for nonlinear kinetics [Cnew =
Copyright © 2014 McGraw-Hill Education. All rights reserved.
69
Vmax
Slope = −Km
e|CHAPTER  
DR
DR/Css
5
Clinical Pharmacokinetics and Pharmacodynamics
eFigure 5-13  Relationship between dosage rate (DR) and
steady-state serum concentrations (Css).
1.15(12.3 mcg/mL) = 14.1 mcg/mL or Cnew = 1.33 (12.3 mcg/mL) =
16.4 mcg/mL]. Thus, the patient would be expected to have a steady-
state phenytoin concentration of approximately 14 to 16  mcg/mL
(14 to 16 mg/L; 56 to 63 μmol/L) as a consequence of the dosage
increase. An alternative approach would be to use a graphic Bayes-
ian method that allows an estimate of Vmax and Km from one steady-
state phenytoin concentration and the prediction of new steady-state
concentrations when doses are changed.55
Other methods used to individualize phenytoin doses involve
rearrangements of the Michaelis-Menten equation [DR = VmaxCss/
(Km + Css), in which DR is the dosage rate at steady state] so that two
or more doses and Css values can be used to obtain graphic solutions
for Vmax and Km. One rearrangement56 is DR = -Km(DR/Css) + Vmax.
When DR is plotted on the y axis, and DR/Css is plotted on the x axis
of Cartesian graph paper, a straight line with a y intercept of Vmax
and slope equal to -Km is found (eFig. 5-13). To use this method,
patients are prescribed an initial phenytoin dose, and Css is obtained.
The phenytoin dose is then changed, and a second Css from the new
dose is obtained. Each dose is divided by its respective Css to derive
DR/Css values. The DR/Css and Css values are plotted on the graph to
calculate Vmax (y intercept) and Km (minus slope). The steady-state
Michaelis-Menten equation can be used to compute Css.
Cyclosporine
Because of the large amount of variability in cyclosporine pharma-
cokinetics, even when concurrent disease states and conditions are
identified, many clinicians believe that the use of standardized initial
cyclosporine doses for various situations is warranted. Indeed, most
transplant centers use doses that are determined employing a locally
derived cyclosporine dosage protocol. The original computations
of these doses were based on the pharmacokinetic dosing methods
described in preceding sections and subsequently modified based on
clinical experience. In general, the expected cyclosporine Css used to
compute these doses depends on the type of transplanted tissue and
the posttransplantation time line. Generally speaking, initial oral
doses of 8 to 18 mg/kg daily or IV doses of 3 to 6 mg/kg daily (one-
third the oral dose to account for ∼30% oral bioavailability) are used
and vary greatly from institution to institution. For obese individuals
(>30% over ideal body weight), ideal body weight should be used to
compute initial doses.
It is likely that doses computed using patient population
characteristics will not always produce cyclosporine concentra-
tions that are expected or desirable. Additionally, there is a very
high amount of interday variation in cyclosporine concentrations.
 70
eTable 5-7 Recommended 2-hour (±15 min) Postdose CLINICAL PHARMACODYNAMICS
Steady-state Cyclosporine Concentrations
(C2) for Various Solid Organ Transplant 16 Pharmacodynamics is the study of the relationship between
Types and Posttransplant Times the concentration of a drug and the response obtained in a patient.
Renal Transplant
Originally, investigators examined the dose–response relationship
posttransplant Time (Months) C2 Level
of drugs in humans but found that the same dose of a drug usually
resulted in different concentrations in individuals because of phar-
1 1,500–2,000 ng/mL or mcg/L
1,248-1,664 nmol/L macokinetic differences in clearance and volume of distribution.
Examples of quantifiable pharmacodynamic measurements include
SECTION

2 1,500 ng/mL or mcg/L

1,248 nmol/L changes in blood pressure during antihypertensive drug therapy,
decreases in heart rate during β-blocker treatment, and alterations in
3 1,300 ng/mL or mcg/L
1,082 nmol/L prothrombin time or international normalized ratio during warfarin
therapy.
  

4–6 1,100 ng/mL or mcg/L

915 nmol/L For drugs that exhibit a direct and reversible effect, the follow-
1 7–12 900 ng/mL or mcg/L
ing diagram describes what occurs at the level of the drug receptor:
749 nmol/L
Drug + receptor ↔ drug - receptor complex ↔ response
>12 800 ng/mL or mcg/L
Foundation Issues

666 nmol/L According to this scheme, there is a drug receptor located

Liver Transplant
Posttransplant Time (Months) C2 Level
0–3 1,000 ng/mL or mcg/L
832 nmol/L
4–6 800 ng/mL or mcg/L
666 nmol/L
>6 600 ng/mL or mcg/L
499 nmol/L
Data from References 57, 58, and 59.
Because of pharmacokinetic variability, the narrow therapeutic
index of cyclosporine, and the severity of cyclosporine adverse side
effects, measurement of cyclosporine concentrations is mandatory
for patients to ensure that therapeutic, nontoxic levels are present.
When cyclosporine concentrations are measured in patients, and a
dosage change is necessary, clinicians should seek to use the sim-
plest, most straightforward method available to determine a dose
that will provide safe and effective treatment. In most cases, a sim-
ple dosage ratio can be used to change cyclosporine doses using
steady-state concentrations and assuming that the drug follows lin-
ear pharmacokinetics:
Css,new
Dnew = Dold
Css,old
The Css can be either a steady-state trough concentration or a
Css measured 2 hours (±15 min) after a dose (C2). When C2 levels
are used, recommended concentrations vary according to transplant
type and posttransplant time (see eTable 5-7).57–59
For example, LK is a 50-year-old, 75 kg (165 lb), 5 ft 11 in.
(71  in. [180 cm]) male renal transplant recipient who is receiv-
ing oral cyclosporine 400 mg every 12 hours. The current steady-
state blood cyclosporine concentration is 375 ng/mL (375 mcg/L;
312  nmol/L). To compute a cyclosporine dose that will provide a
Css of 200 ng/mL (200 mcg/L; 166 nmol/L), linear pharmacokinetic
within the target organ or tissue. When a drug molecule “finds” the
receptor, it forms a complex that causes the pharmacologic response
to occur. The drug and receptor are in dynamic equilibrium with the
drug–receptor complex.
The Emax and Sigmoid Emax Models
The mathematical model that comes from the classic drug receptor
theory shown previously is known as the Emax model:
Emax × C
E=
EC 50 + C
where E is the pharmacologic effect elicited by the drug, Emax is
the maximum effect the drug can cause, EC50 is the concentration
causing one-half the maximum drug effect (Emax/2), and C is the
concentration of drug at the receptor site. EC50 can be used as a mea-
sure of drug potency (a lower EC50, indicating a more potent drug),
whereas Emax reflects the intrinsic efficacy of the drug (a higher
Emax, indicating greater efficacy). If pharmacologic effect is plotted
against concentration in the Emax equation, a hyperbola results with
an asymptote equal to Emax (eFig. 5-14). At a concentration of zero,
no measurable effect is present.
When dealing with human studies in which a drug is adminis-
tered to a patient, and pharmacologic effect is measured, it is very
difficult to determine the concentration of the drug at the recep-
tor site. Because of this, serum concentrations (total or unbound)
100
80
60
Effect

equations can be used. The new dose to attain the desired concentra-
40
tion should be proportional to the old dose that produced the mea-
sured concentration (total daily dose = 400 mg/dose × 2 doses/d =
800 mg/d): 20

Css,new 200 ng/mL

Dnew = Dold = 800 mg/day
Css,old 375 ng/mL
0 50 100 150 200 250 300 350
= 427 mg/day, round to 400 mg/day Concentration

The new suggested dose would be 400 mg/day or 200 mg every eFigure 5-14  The Emax model [E = (Emax × C)/(EC50 + C)] has the
12 hours of cyclosporine capsules to be started at the next scheduled shape of a hyperbola with an asymptote equal to Emax. EC50 is the
dosing time. concentration where effect = Emax/2.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 71
usually are used as the concentration parameter in the Emax equation. 80
Therefore, the values of Emax and EC50 are much different than if
the drug were added to an isolated tissue contained in a laboratory
beaker. 60
The result is that a much more empirical approach is used to
describe the relationship between concentration and effect in clini-
cal pharmacology studies. After a pharmacodynamic experiment

Effect
40

e|CHAPTER  
has been conducted, concentration–effect plots are generated. The
shape of the concentration–effect curve is used to determine which
pharmacodynamic model will be used to describe the data. Because
20
of this, the pharmacodynamic models used in a clinical pharmacol-
ogy study are deterministic in the same way that the shape of the
serum-concentration-versus-time curve determines which pharma-
cokinetic model is used in clinical pharmacokinetic studies. 0 10 20 30 40 50 60 70 80
Sometimes a hyperbolic function does not describe the
­concentration–effect relationship at lower concentrations adequately.
Concentration 5
When this is the case, the sigmoid Emax equation may be supe- eFigure 5-16  The linear model (E = S × C + I) is often used as a

Clinical Pharmacokinetics and Pharmacodynamics

rior to the Emax model:
Emax × C n
E=
EC n50 + C n
where n is an exponent that changes the shape of the ­concentration–
effect curve. When n > 1, the concentration–effect curve is S- or
sigmoid-shaped at lower serum concentrations. When n < 1, the
­concentration–effect curve has a steeper slope at lower concentra-
tions (eFig. 5-15).
With both the Emax and sigmoid Emax models, the largest
changes in drug effect occur at the lower end of the concentra-
tion scale. Small changes in low serum concentrations cause large
changes in effect. As serum concentrations become larger, further
increases in serum concentration result in smaller changes in effect.
Using the Emax model as an example and setting Emax = 100 units
and EC50 = 20 mg/L, doubling the serum concentration from 5 to
10 mg/L increases the effect from 20 to 33 units (a 67% increase),
whereas doubling the serum concentration from 40 to 80 mg/L only
increases the effect from 67 to 80 units (a 19% increase). This is an
important concept for clinicians to remember when doses are being
titrated in patients.
Linear Models
When serum concentrations obtained during a pharmacodynamic
experiment are between 20% and 80% of Emax, the concentration–
effect curve may appear to be linear (eFig. 5-16). This occurs often
100
80
60
Effect
pharmacodynamic model when the measured pharmacologic
effect is 20% to 80% of Emax. In this situation, the determination
of Emax and EC50 is not possible. To illustrate this, effect
measurements from eFigure 5-14 between 20% and 80% of Emax
are graphed using the linear pharmacodynamic model.
because lower drug concentrations may not be detectable with the
analytic technique used to assay serum samples, and higher drug
concentrations may be avoided to prevent toxic side effects. The
equation used is that of a simple line: E = S × C + I, where E is the
drug effect, C is the drug concentration, S is the slope of the line, and
I is the y intercept. In this situation, the value of S can be used as a
measure of drug potency (the larger the value of S, the more potent
the drug). The linear model can be derived from the Emax model.
When EC50 is much greater than C, E = (Emax/EC50)C = S × C, where
S = Emax/EC50.
The linear model allows a nonzero value for effect when the
concentration equals zero. This may be a baseline value for the
effect that is present without the drug, the result of measurement
error when determining effect, or model misspecification. Also, this
model does not allow the prediction of a maximum response.
Some investigators have used a log-linear model in pharma-
codynamic experiments: E = S × (log C) + I, where the symbols
have the same meaning as in the linear model. The advantages
of this model are that the concentration scale is compressed on
­concentration–effect plots for experiments where wide concentra-
tion ranges were used, and the concentration values are transformed
so that linear regression can be used to compute model parameters.
The disadvantages are that the model cannot predict a maximum
effect or an effect when the concentration equals zero. With the
increased availability of nonlinear regression programs that can
compute the parameters of nonlinear functions such as the Emax
model easily, use of the log-linear model has been discouraged.60
Baseline Effects

40 At times, the effect measured during a pharmacodynamic study

has a value before the drug is administered to the patient. In these
cases, the drug changes the patient’s baseline value. Examples of
20
these types of measurements are heart rate and blood pressure. In
addition, a given drug may increase or decrease the baseline value.
Two basic techniques are used to incorporate baseline values into
0 50 100 150 200 250 300 350
Concentration
pharmacodynamic data. One way incorporates the baseline value
into the pharmacodynamic model; the other transforms the effect
eFigure 5-15  The sigmoid Emax model [E = (Emax × Cn)/(ECn50 + Cn)] data to take baseline values into account.
has an S-shaped curve at lower concentrations. In this example, Incorporation of the baseline value into the pharmacodynamic
Emax and EC50 have the same values as in eFigure 5-14. model involves the addition of a new term to the previous equations.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
 72
E0 is the symbol used to denote the baseline value of the effect that
will be measured. The form that these equations takes depends
on whether the drug increases or decreases the pharmacodynamic
effect. When the drug increases the baseline value, E0 is added to
the equations:
Emax × C
E = E0 +
EC50 + C
Emax × C n
SECTION
E = E0 +
EC n50 + C n
E = S × C + E0
When E0 is not known with any better certainty than any other
effect measurement, it should be estimated as a model parameter
1 similar to the way that one would estimate the values of Emax, EC50,
S, or n.61,62 If the baseline effect is well known and has only a small
amount of measurement error, it can be subtracted from the effect
Foundation Issues
determined in the patient during the experiment and not estimated
as a model parameter. This approach can lead to better estimates
of the remaining model parameters.62 Using the linear model as an
example, the equation used would be E - E0 = S × C.
If the drug decreases the baseline value, the drug effect is sub-
tracted from E0 in the pharmacodynamic models:
Emax × C
E = E0 –
IC50 + C
Emax × C n
E = E0 –
IC n50 + C n
E = E0 – S × C
where Emax represents the maximum reduction in effect caused by
the drug, and IC50 is the concentration that produces a 50% inhibi-
tion of Emax. These forms of the equations have been called the inhib-
itory Emax and inhibitory sigmoidal Emax equations, respectively. In
this arrangement of the pharmacodynamic model, E0 is a model
parameter and can be estimated. If the baseline effect is well known
and has little measurement error, the effect in the presence of the
drug can be subtracted from the baseline effect and not estimated as
a model parameter. Using the inhibitory Emax model as an example,
the formula would be E0 - E = (Emax × C)/(IC50 + C).
When using the inhibitory Emax model, a special situation occurs
if the baseline effect can be obliterated completely by the drug (e.g.,
decreased premature ventricular contractions during antiarrhythmic
therapy). In this situation, Emax = E0, and the equation simplifies to a
rearrangement known as the fractional Emax equation:
E = E0 1 – C 
 IC50 + C 
This form of the model relates drug concentration to the frac-
tion of the maximum effect.
An alternative approach to the pharmacodynamic modeling
of drugs that alter baseline effects is to transform the effect data
so that they represent a percentage increase or decrease from the
baseline value.62 For drugs that increase the effect, the following
transformation equation would be used: percent effectt = [(treat-
mentt - baseline)/baseline] × 100. For drugs that decrease the
effect, the following formula would be applied to the data: percent
inhibitiont = [(baseline - treatmentt)/baseline] × 100. The subscript
indicates the treatment, effect, or inhibition that occurred at time
t during the experiment. If the study included a placebo control
phase, baseline measurements made at the same time as treatment
measurements (i.e., heart rate determined 2 hours after placebo
and 2 hours after drug treatment) could be used in the appropriate
transformation equation.62 The appropriate model (excluding E0)
then would be used.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
80
70
60
50
Effect
40
30
20
10
0 20 40 60 80
Concentration
100 120 140
eFigure 5-17  Hysteresis occurs when effect measurements
are different at the same concentration. This is commonly
seen after short-term IV infusions or extravascular doses
where concentrations increase and subsequently decrease.
Counterclockwise hysteresis loops are found when
concentration–effect points are joined as time increases (shown
by arrows) and effect is larger at the same concentration but
at a later time. Clockwise hysteresis loops are similar, but the
concentration–effect points are joined in clockwise order, and
the effect is smaller at a later time.
Hysteresis
Concentration–effect curves do not always follow the same pat-
tern when serum concentrations increase as they do when serum
concentrations decrease. In this situation, the concentration–effect
curves form a loop that is known as hysteresis. With some drugs, the
effect is greater when serum concentrations are increasing, whereas
with other drugs, the effect is greater while serum concentrations are
decreasing (eFig. 5-17). When individual concentration–effect pairs
are joined in time sequence, this results in clockwise and counter-
clockwise hysteresis loops.
Clockwise hysteresis loops usually are caused by the devel-
opment of tolerance to the drug. In this situation, the longer the
patient is exposed to the drug, the smaller is the pharmacologic
effect for a given concentration. Therefore, after an extravascular
or short-term infusion dose of the drug, the effect is smaller when
serum concentrations are decreasing compared with the time
when serum concentrations are increasing during the infusion or
absorption phase.
Accumulation of a drug metabolite that acts as an antagonist
also can cause clockwise hysteresis.
Counterclockwise hysteresis loops can be caused by the accu-
mulation of an active metabolite, sensitization to the drug, or delay
in time in equilibration between serum concentration and concentra-
tion of drug at the site of action. Combined pharmacokinetic/phar-
macodynamic models have been devised that allow equilibration lag
times to be taken into account.
SUMMARY
The availability of inexpensive, rapidly achievable serum drug con-
centrations has changed the way clinicians monitor drug therapy in
patients. The therapeutic range for many drugs is known, and it is
likely that more drugs will be monitored using serum concentra-
tions in the future. Clinicians need to remember that the therapeu-
tic range is merely an average guideline and to take into account
interindividual pharmacodynamic variability when treating patients.

Individual patients may respond to smaller concentrations or require
concentrations that are much greater to obtain a therapeutic effect.
Conversely, patients may show toxic effects at concentrations within
or below the therapeutic range. Serum concentrations should never
replace clinical judgment.
Three kinetic constants determine the dosage requirements of
patients. Clearance determines the maintenance dose (MD = CLCss),
volume of distribution determines the loading dose (LD = VDCss),
and half-life determines the time to steady state and the dosage
interval. Several methods are available to compute these parameters.
Methods available to individualize drug therapy range from
clinical pharmacokinetic techniques using simple mathematical
relationships that hold for all drugs that obey linear pharmaco-
kinetics to very complex computer programs that are specific to
one drug.
ABBREVIATIONS
ALT alanine aminotransferase
AST aspartate aminotransferase
AUC area under the concentration-versus-time curve
CHF chronic heart failure
CL clearance
CLcr creatinine clearance
CLcr est estimated creatinine clearance
CLR renal clearance
Cmax maximum serum or blood concentrations
Css steady-state drug concentration
CYP cytochrome P450
D dose
DR dosage rate
Emax the maximum pharmacologic effect elicited by a drug
GI gastrointestinal
ka absorption rate constant
LD loading dose
MIC minimum inhibitory concentration
P-gp P-glycoprotein
t1/2 half-life
VD volume of distribution
Vmax maximum rate of metabolism
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